Review Article Understanding Idiopathic Interstitial ...downloads.hindawi.com/journals/bmri/2015/304186.pdf · [, ]. ese numbers may even be an underestimation, because the studies

Review ArticleUnderstanding Idiopathic Interstitial PneumoniaA Gene-Based Review of Stressed Lungs

Coline H M van Moorsel12 Thijs W Hoffman1 Aernoud A van Batenburg1 Dymph Klay1

Joanne J van der Vis13 and Jan C Grutters12

1Center for Interstitial Lung Disease Department of Pulmonology St Antonius HospitalPO Box 2500 3430 EM Nieuwegein Netherlands2Division of Heart and Lung University Medical Center Utrecht PO Box 85500 3508 GA Utrecht Netherlands3Center for Interstitial Lung Disease Department of Clinical Chemistry St Antonius HospitalPO Box 2500 3430 EM Nieuwegein Netherlands

Correspondence should be addressed to Coline H M van Moorsel cvanmoorselantoniusziekenhuisnl

Received 19 June 2015 Accepted 26 August 2015

Academic Editor Shinichiro Ohshimo

Copyright copy 2015 Coline H M van Moorsel et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Pulmonary fibrosis is the main cause of severe morbidity and mortality in idiopathic interstitial pneumonias (IIP) In the pastyears there has been major progress in the discovery of genetic factors that contribute to disease Genes with highly penetrantmutations or strongly predisposing common risk alleles have been identified in familial and sporadic IIP This review summarizesgenes harbouring causative rare mutations and replicated common predisposing alleles To date rare mutations in nine differentgenes and five risk alleles fulfil this criterion Mutated genes represent three genes involved in surfactant homeostasis and six genesinvolved in telomere maintenance We summarize gene function gene expressing cells and pathological consequences of geneticalterations associated with disease Consequences of the genetic alteration include dysfunctional surfactant processing ER stressimmune dysregulation andmaintenance of telomere length Biological evidence shows that these processes point towards a centralrole for alveolar epithelial type II cell dysfunction However tabulation also shows that function and consequence of most commonrisk alleles are not knownMost importantly the predisposition of theMUC5B risk allele to disease is not understoodWe propose amechanism whereby MUC5B decreases surface tension lowering capacity of alveolar surfactant at areas with maximal mechanicalstress

1 Idiopathic Interstitial Pneumonia

Idiopathic interstitial pneumonias (IIP) are a class of diffuselung diseases comprising several distinct entities Idiopathicpulmonary fibrosis (IPF) is the most common and severeform of IIP Median survival in IPF is 3 years [1] Otherless common entities include nonspecific interstitial pneu-monia (NSIP) desquamative interstitial pneumonitis (DIP)and cryptogenic organizing pneumonia (COP) Distinctionbetween the different entities of IIP is important with regardto prognosis and therapeutic decision-making includingtiming of lung transplantation or palliative care Howevergenetic discoveries have raised the question whether thevarious types of IIP are in fact different diseasemanifestationswithin the same pathogenetic spectrum [2] In a large cohort

of patients with familial interstitial pneumonia (FIP) it wasfound that a diagnosis of IPF was most frequent but allsubtypes of IIP were represented [3] Furthermore althoughit is commonly assumed that IPF does not and non-IPF IIPdoes respond to immunosuppressive treatment part of thenon-IPF IIP patient population are refractory to treatmentand progress to end-stage fibrosis with severely reducedsurvival [4]

2 Familial Disease

All human phenotypes including disease phenotypes areinfluenced by a personrsquos genetic constitution In case of IIPevidence for a more defining genetic contribution to diseaseis most compelling Ethnic differences in incidence of IPF

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 304186 13 pageshttpdxdoiorg1011552015304186

2 BioMed Research International

include higher occurrence in Hispanics than in Whites andthe lowest occurrence in Blacks and Maori [5 6] In theoryfamilial occurrence may well be explained by presence ofa common environmental cause An environmental causerequires clustering of affected family members in spaceand time while a genetic cause allows for differences inspace and time Such differences are frequently observed infamilial IIP including sibs from different environments andparent-offspring disease with an interval of decades [3 7ndash9] and support the involvement of heritable factors IIP isfamilial in approximately 10 of cases [10] and might evenreach 20 in cohorts with IPF or end-stage lung disease[11 12] These numbers may even be an underestimationbecause the studies relied on patient reports With moreelaborate measurement of familial disease an even largerfamilial component can be identified Scholand and cowork-ers performed an extraordinary study for which they firstidentified 1000 cases that died from pulmonary fibrosis inthe Utah Population Database They showed that the averagerelatedness of these 1000 cases was significantly higher thanthat of matched controls even when first- and second-degreerelatives were excluded [13]

3 Alveolar Epithelial Type II Cell

A major breakthrough was achieved when the first causativemutation was identified in a family with IIP Candidategene sequencing detected a heterozygous mutation in surfac-tant protein C (SFTPC) [14] Because SFTPC is exclusivelyexpressed in type II alveolar epithelial cells (AECs) it wasproof that erroneous processes in AEC type II could ulti-mately lead to pulmonary fibrosis

The reported family already contained many featuresof disease associated with SFTPC mutations familial ILDdominant expression variable penetrance and expressivityresulting in acute and chronic lung disease in individualsranging from newborn to adult [10 15 16] Since the firstdiscovery many IIP families with surfactant mutations havenow been described SFTPC mutations are now establishedas an important cause of paediatric ILD but also known tocontribute to predominantly familial IIP in adults [10 17ndash19] Table 1 summarizes characteristics of mutated genes inIIP and biological consequences of mutations

4 Surfactant Processing

After transcription and translation of SFTPC in AEC type IIa proprotein is formed which after subsequent folding andcleavage steps becomes a mature surfactant protein readyfor secretion into the alveolar space via lamellar bodiesPulmonary surfactant consists of a mixture of lipids andspecific proteins that lowers alveolar surface tension therebypreventing alveolar collapse at the end of expiration [20 21]

Erroneous SFTPC processing is currently one of the beststudied mechanisms leading to IIP The consequence of amutation in SFTPC depends on its position in the gene [22]

Mutations in the C-terminal BRICHOS domain generallyincrease endoplasmic reticulum (ER) stress and activate theunfolded protein response (UPR) in AEC type II [23ndash26]

In turn ER stress can induce epithelial-to-mesenchymaltransition in lung epithelial cells [24]

The role of ER stress is not limited to SFTPC mutationcarriers as different studies showed that AECs in fibrotictissue from nonmutated FIP and sporadic IPF patients werealso positive for ER-stress markers [23 27]

The most common SFTPC mutation is I73T and doesnot cause substantial elevation of ER stress [28] It repre-sents a linker domain mutation that alters trafficking of thepropeptide to early endosomes [29] and causes dysregulatedproteostasis [30] Furthermore alteration of the surfactantlipid composition and activation of immune cells are reportedfor these mutations [31]

Later mutations in a second surfactant associated genesurfactant protein A2 (SFTPA2) were identified in twofamilies Family members presented with adult early-onsetpulmonary fibrosis or lung cancer with features of bronchi-oloalveolar carcinoma [32] Surfactant protein A2 is a C-typelectin important in the defense against respiratory pathogensand in the lung It is expressed not only by AEC type IIbut also by Clara cells and submucosal glands [33 34] Themutant protein when expressed in AECs was not excretedbut retained in the ER and induced ER stress [35] a processsimilar to that seen in SFTPC mutants However there areno reports on lung cancer in patients with SFTPC mutationER stress is linked to tumorigenesis [36] and tumorigenesisin BAC is often thought to involve Clara cells [37]

5 Lamellar Bodies

Lamellar bodies are secretory organelles unique to type IIAECand are crucial for biosynthetic processing and transportof pulmonary surfactant Proteins of the limiting membraneof lamellar bodies are encoded by the gene ABCA3 In thelung the highest expression of ABCA3 has been observed intype II AEC and corresponds with the presence of lamellarbodies [20] Recessive mutations in ABCA3 are the mostcommon genetic cause of lethal surfactant deficiency inneonates or chronic ILD in children [38ndash40]

In type II AECs ABCA3 mutations cause abnormal pro-cessing trafficking and functionality of the ABCA3 protein[41 42] resulting in impaired lipid transport [43] or retentionin the ER compartment and elevated ER stress and apoptoticsignaling [44] Only recently were compound heterozygousor homozygous mutations in ABCA3 described in adult IIP[45 46] A French patient with ABCA3 mutations presentedwith combined pulmonary fibrosis and emphysema (CPFE)[46] CPFE typically occurs inmale smokers but also has sim-ilarities to radiographs of IIP patients with SFTPCmutations[47] Dysfunctional lamellar bodies in AEC type II were alsoidentified as a cause of pulmonary fibrosis in Hermansky-Pudlak Syndrome (HPS)

HPS is a systemic disorder characterized by reducedpigmentation of skin hair and eyes and bleeding diathesisDisease is caused by autosomal recessive mutations in thegene HPS1 [48] that lead to giant lamellar bodies in type IIAECs with a deficiency to fuse with the outer cell membraneand excrete lamellar body content [49ndash51] Pulmonary fibro-sis in HPS shares many similarities with that observed in IPF

BioMed Research International 3

Table1Mutated

genesinIIPexpressin

gpu

lmon

arycellsfun

ction

andmutationalcon

sequ

ences

Gene

Expressin

gcells

inlung

Genefun

ctionlowast

Mutated

domain

Effecto

fmutation

Pathologicalprocess

SFTP

CAEC

type

II[107]

Com

ponent

ofsurfa

ctant

fluid

Lower

surfa

cetension[107]

Link

erdo

mainassociates

with

LB[31]

Toxicg

ainof

functio

n[107]

Alteratio

nof

traffi

cking

dysregulationof

proteosta

sis[31]

Alteratio

nof

surfa

ctantlipid

compo

sition[31]

C-term

inalBR

ICHOS

domainfolded

inER

and

GA[108]

ERstr

essa

ndUPR

upregu

latio

n[109ndash111]

Activ

ationof

immun

ecells[112]

Alteratio

nof

surfa

ctantlipid

compo

sition[112]

SFTP

A2

AEC

type

IIClaraclu

bcell

Subm

ucosalgland

[113ndash116]

Collectin

(tomod

ulate

innateandadaptiv

eim

mun

ity)[107117

]

Carboh

ydrate-recognitio

ndo

main[32]

Toxicg

ainof

functio

n[118]

Increase

ofER

stress[118

]UPR

upregu

latio

n[35119

]

ABCA

3AEC

type

II[120]

Limiting

mem

branep

rotein

oflamellarb

ody[107]

Intracellularloo

pextracellulard

omain2

[4546

121]

Lossof

functio

nTo

xicg

ainof

functio

n[107]

Abno

rmalsurfa

ctant

processin

gtraffi

cking[45122]

Lossof

epith

elialfunctio

n[41]

Increase

ofER

stress[4144]

TERT

AEC

type

II[123]

Lung

fibroblasts

[124125]

Lung

epith

elialcells

[126]

Enzymeintelomerase

complex

maintaining

telomerelength[127ndash130]

All[555660131ndash135]

Haploinsufficiency

[56136137]

Telomeres

hortening

[55566162124131138139]

TERC

AEC

type

II[70123140]

Lung

fibroblasts

[124125]

Templateintelomerase

complex

[127ndash130]

Pseudo

knotC

R4-C

R5and

ScaR

NAdo

mains

[555661133139141142]

Haploinsufficiency

[136137143144

]Telomeres

hortening

[555661124131138]

DKC

1Lu

ngtissue[145]

Dyskerin

(stabilizes

templateintelomerase

complex)[64

]

NearR

NA-

bind

ingdo

main

[64]nearN

-term

inus

[146ndash

149]

X-lin

kedlossof

functio

n[64]

Telomeres

hortening[64]

DecreaseinTE

RC[14

6]

TINF2

Lung

tissue[150]

Telomerem

aintenance

byshelterin

complex

[151]

Exon

6resid

ues2

69ndash298

[63152153]

Dom

inantn

egative[63]

Telomeres

hortening[63]

RTEL

1Not

detectablein

lung

s[154155]

DNAhelicasetelomere

T-loopand

G4un

winding

[156]

Vario

usdo

mainsthatis

helicasea

ndharm

onin

[65ndash67157]

Haploinsufficiency

[66]

Telomeres

hortening[65ndash67]

PARN

Lung

tissue[158]

Exoribon

ucleasec

ontro

lsmRN

Astability[159]

MainlyCA

F1rib

onuclease

domain[67]

Haploinsufficiency

[67]

Telomeres

hortening[67]

Redu

ctionof

DKC

1TE

RT

TERC

and

TERF

1[159]

lowast

Genefun

ctionsuggestedto

beinvolved

inIIPpathogenesis


[52 53] Due to unfamiliaritywith the disease and the variabledegree of albinism and bleeding disorders misdiagnosismight occur However clinical features characteristic forHPSare scars in pulmonary fibrosis In a cohort study including127 patients with pulmonary fibrosis only four patients hadtwo or more features consistent with HPS One out of fourhad HPS and was compound heterozygous for mutations inHPS1 Review of her medical documentation showed that shehad received a diagnosis of IPF prior to referral to a tertiarycenter [54]

6 Telomere Maintenance

A different set of genes involved in FIP was discovered whenanamnestic familial [55] and genome-wide linkage [56] anal-ysis linked IIP to mutations in the genes TERT and TERCThe gene TERT encodes telomerase reverse transcriptasewhich together with the transcript of the telomerase RNAcomponent (TERC) forms the telomere complex required tomaintain telomere length

Mutations in the telomerase genes have been found tocause a telomere syndrome with one or more manifesta-tions of early aging such as idiopathic pulmonary fibrosisbone marrow failure or cryptogenic liver cirrhosis [57] Amutation in one TERT allele can lead to haploinsufficiencythat results in overall decreased telomerase activity and ismanifested as premature aging disorders Approximately halfof the mutations (10 out of 19) have less than 40 loss oftelomerase function In a heterozygous individual carryingone wild type and one mutant allele this would result inldquonormalrdquo gt80 overall telomerase activity [58] Howevercarriers of mutations that cause a minor decrease in overalltelomerase activity were shown to cause significant reductionof telomere length over generations that will eventually leadto telomere syndromes [55 56 59] It is not the presence of themutation per se but the length of telomeres that confers therisk for disease Because telomere length is heritable carriageof slightly dysfunctional alleles will over generations leadto pathologically short telomeres a phenomenon known asgenetic anticipation

Leukocytes telomere lengths in cohorts of FIP and spo-radic IIP patients were significantly shorter compared toage-matched controls [60 61] Although this is interestingacquired telomere shortening is a common feature of diseasein humans and recently it was shown that all ILD patientcohorts have shorter telomere length than controls Howeverpatients with sporadic IPF had significantly shorter telomeresthan patients with other forms of IIP or patients with surfac-tant mutations [62] This suggests that telomere shorteningis a common denominator of patients with ILD but telomeredysfunction is only key to IPF

7 Alveolar Epithelial Type II Cell Senescence

Although telomerase has much more functions than main-tenance of telomere length these are not suggested to playa major role in the pathogenesis of IIP The prominentrole of telomere length instead of telomerase is underlinedby the observed genetic anticipation in congruence with

development of disease phenotypes Furthermore recentlyanother four genes TINF2 DKC1 RTEL1 and PARNinvolved in telomere maintenance have been discovered toharbor mutations associated with IIP [63ndash67] Altogetherthis points towards maintenance of telomere length as theunifying cause and not the secondary functions of theindividual genes

AECs type II are responsible for growth differentiationand repair in alveoli [68] In case of alveolar injury AEC typeII cells proliferate along the alveolar basementmembrane anddifferentiate in AEC type I [69]

Recently it was shown that critically short telomeresin AEC type II preferentially induce cellular senescence[70] Such cell cycle alterations are mediated by p53 andp21 Increased levels of p53 and p21 have been observed inhyperplastic AECs in IPF patients [71] and polymorphismsin these genes were shown to associate with disease devel-opment in IPF [72] Cellular senescence of type II AECcaused regenerative defects inflammatory responses andsusceptibility to injury inmice lungs andmice lung organoids[70] This strongly implicates type II AEC senescence as acausative mechanism in IIP pathogenesis

8 Common Risk Alleles

At the outset of genetic studies at the end of the lastcentury pulmonary fibrosis was thought to result from achronic inflammatory process It was therefore logical thatcytokine genes were among the first candidate genes studied[73] Only one gene from that period interleukin-1 receptorantagonist (IL1RN) the gene encoding interleukin-1 receptorantagonist (IL-1Ra) now fulfills our criterion of independentreplication although both positive and negative associationshave been published [74ndash77] A meta-analysis includingall five cohorts showed that carriage of IL1RN VNTRlowast2predisposed to IPF with an odds ratio of 16 [78] The riskallele associates with a reduction of the IL-1Ra to IL-1120573 ratioand thereby causes a profibrotic environment In vivo thiseffect can be counteracted with addition of IL-1Ra whichwas shown to prevent fibrogenesis in mice with bleomycininduced fibrosis [79] Mutations in IL1RN cause deficiencyin IL-1Ra which result in systemic life-threatening neonatalautoinflammatory disease [80] Local deviations of desiredIL-1Ra levels might be associated with the autoinflammatoryenvironment that is seen in IPF lung and is not responsiveto immunosuppressive therapy Immunosuppressive therapysuppresses IL-1Ra synthesis [81] and has been shown to beharmful in IPF [82] All other evidence for the involvementof common genetic variants in IIP is the result of hypothesis-free genome-wide studies The common genetic variantsthat have been associated with IIP in multiple independentcohorts are shown in Table 2

9 Genome-Wide Studies

Genome-wide linkage and fine-mapping identified theminorallele of rs35705950 to be associated with disease in bothFIP and IPF rs35705950 is situated in the putative promoterof MUC5B and the risk allele was shown to correlate with


Table 2 Genes with polymorphisms predisposing to IIP in multiple studies expressing pulmonary cells function and mutational conse-quences

Gene Expressing cells inlung Gene function Risk allele Effect of risk

allele Cellular consequence

IL1RN

Bronchus epithelium[160]Alveolar epithelium[161]Immune cells [162]

Inhibitor ofproinflammatoryeffect of IL-1120572 andIL-1120573 [163]

VNTRlowast2 haploblock[78]

Decreasedexpression [78]

Increase ofIL-1120573Il-1Ra ratiowith proinflamma-toryfibrotic effect[74]

TERT

AEC type II [123]Lung fibroblasts [124]Lung epithelial cells[126]

Enzyme in telomerasecomplex maintainingtelomere length[127ndash130]

rs2736100 major Aallele [86 97 98 164]

MUC5BAirway submucosalglands [165]Macrophages [166]

Influence onrheological propertiesof airway mucusmucociliarytransport and airwaydefense [93 165]

rs35705950 minor Tallele[83 84 86 87 96 98100 164 167ndash169]

Expression uarr[83]

Lower bacterialburden [93 94]Improvedmacrophage function[93]

LRRC34 Not detected inhuman lung [170] rs6793295 minor C

allele [86 98]

FAM13A Lung tissue [99] rs2609255 minor Gallele [86 98]

No upregulationin lung tissue[98]

IVD

Mitochondrial matrixenzyme involved inleucine catabolism[98]

rs2034650 major Tallele [86 98]


Pooled meta-analysis of five independent cohorts [74ndash77]

increased MUC5B expression in lung from unaffected sub-jects [83] Carriage of the risk allele conferred high odds ratioswell over five [83 84] Such high odds ratios in genome-wideanalyses are seldom found and would usually involve rarevariants [85] However the minor allele of rs35705950 is notrare in Caucasian cohorts where the population frequency isapproximately 10

In African Yoruban African American and Asian pop-ulations risk allele frequencies are rare and vary between 0and 3 (httpwwwncbinlmnihgovprojectsSNPsnp refcgirs=35705950) The contribution to disease of the riskallele in these cohorts is still under investigation [86 87]Interestingly the SNPwas recently shown to be associated notonly with IPF but also with NSIP in a small German cohortwhich suggests that IPF and NSIP have similar pathogenesiswith regard to MUC5B [87]

10 Airway Involvement

In the lung MUC5B is preferentially expressed by distalairway epithelium but not by alveolar epithelium [88]Several exogenous factors including cigarette smoke andendogenous factors have been shown to increase MUC5Bexpression or decrease clearance in the lung [50 89 90]Chronic airway diseases are commonly accompanied by

raised expression of gel-forming mucins Interestingly inhuman bronchial cells it was shown that proinflammatorycytokines IL-1120573 and IL-17A were potent inducers ofMUC5BmRNA expression The induction by IL-1B was both timeand dose dependent and involved IL-1R1 receptor bindingfollowed by NF-120581B-based transcriptional mechanism [91]

The MUC5B protein is present in IPF lesions and IPFpatients had significantly increased expression of MUC5Bin the lungs compared with controls Changes in MUC5Blevels have been suggested to interfere in alveolar repairin IPF but this needs further investigation [83 92] Moreevidence is available regarding MUC5B dependent changesin pulmonary immune regulation Muc5b deficient micehave impaired mucociliary clearance And absence of Muc5bcaused accumulation of apoptotic macrophages impairedphagocytosis and chronic infection Muc5b overexpressionin mice leads to improved macrophage function [93] InIPF patients carrying the risk allele a lower bacterial burdenwas found suggesting a direct relationship between hostimmunity and bacterial load [94] This beneficiary effect ofthe risk allele corresponds well with significant associationswith improved survival in IPF [95] less severe pathologicalchanges in FIP [92] and slower decline in FVC for IPF [96]All evidence so far points towards a beneficiary effect of therisk allele during disease but its role in disease susceptibilityremains elusive


11 Genome-Wide Association Studies

The first common variant that was associated with IIPthrough a genome-wide association study (GWAS) wasrs2736100 in the TERT gene [97] in a Japanese populationThe association was replicated in a second GWAS includingnon-Hispanic white IIP patients [98] and in aMexican candi-date gene study [86] Furthermore three novel IIP-associatedloci that were identified in the second GWAS were alsoreplicated in the Mexican study polymorphisms rs6793295(LRRC34) rs2609255 (FAM13A) and rs2034650 (IVD)(Table 2) [86] The IVD variant was also associated withIPF in a Korean IPF population [86] For all variants allelefrequencies differed significantly between populations butthe allele associatedwith increased risk for IIPwas consistent

LRRC34 is of unknown function but the LRRC34 geneis located near the TERC gene [98] perhaps indicating anassociation with telomere maintenance Polymorphisms inthe FAM13A gene have been associated with lung function inthe general population as well as with various lung diseasesThe function of FAM13A is unknown but it is speculated thatFAM13A polymorphisms affect rhoGTPases activity possiblyaffecting the lung endothelial barrier [99] The IVD geneencodes a mitochondrial matrix enzyme involved in leucinemetabolism [98] Why an IVD polymorphism is associatedwith IIP remains to be determined

One further largeGWAS conducted byNoth and cowork-ers [100] included IPF patients and controls distributed overthree stagesThere might have been a partial overlay betweencases from this GWAS and the previously mentioned GWASby Fingerlin et al [98] as a proportion of patients wererecruited from the same cohorts This study did not identifynew risk alleles that have been replicated independently

12 Genome Region 11p155

The GWAS by Noth et al [100] identified three polymor-phisms in the TOLLIP gene that were significantly associatedwith IPF TOLLIP is a negative regulator of the TGF-betapathway and interacts with Toll-like receptors and withinterleukin-1 receptor trafficking which makes it an inter-esting candidate gene for IPF susceptibility [100] Howeverthe association with TOLLIP has not been replicated inde-pendently In the GWAS by Fingerlin et al [98] associatedTOLLIP SNPs had also been identified but they discoveredthat the effect disappeared after correction for the effectof MUC5B This suggests that there is linkage disequilib-rium (LD) between TOLLIP and MUC5B Both genes arelocated in the same chromosomal region 11p155 just 12 kbapart (httpwwwncbinlmnihgovgene) Genes separatedby 12 kb are considered to be in very close proximity becausethe expected extension of LD in humans of European origin isat least 60 kb [101] Measures for LD describe the nonrandomassociation of genetic markers based on the frequencies ofthe marker alleles LD is often represented as the correlationcoefficient 1199032 between markers In the study by Noth etal 1199032 between TOLLIP and MUC5B SNPs was found tobe very low 1199032 lt 016 and analysis of TOLLIP wastherefore pursued [100] However another measurement for

linkage disequilibrium 1198631015840 provides information about therecombination breakpoints of chromosomes SNPs with low1199032 values can reside in a linkage disequilibrium block witha high level of 1198631015840 between markers In such a case diseaseassociations are not independent [102] Further studies aretherefore needed to fully understand the contribution of the11p155 region to disease

13 Genes in Disease Pathogenesis

Genetic variations in surfactant associated genes SFTPCSFTPA2 and ABCA3 point out AEC type II dysfunction atthe initiation of disease Coping with additional epithelialdamage requires proliferation of AEC type II with propertelomere maintenance controlled by TERT TERC DKC1TINF2 RTEL1 and PARN In families one mutation thatalters the quality or quantity of any of these genes is enoughto cause pulmonary fibrosis In sporadic patients more subtleeffects of a polymorphism in TERT might steer damage con-trol into a similar direction although this would likely requireadditional damaging environmental or genetic influencesOn the other hand it is more difficult to place the MUC5Bassociation into this model of disease pathogenesis Verifiedeffects of the polymorphism such as increased productionthat enhances the immunological properties of the lungassociate well with the observed beneficial consequences ofcarriership in patients such as increased survival and slowerdecline of lung function However it does not explain thedisease predisposing effect

14 A Unifying Theory MUC5B Alters AlveolarSurfactant Fluid Properties at Areas withMaximal Mechanical Stress

Interestingly theMUC5B risk allele associated with the pres-ence of interstitial lung abnormalities on HRCT in a generalpopulation The association was independent of smokinghistory and stronger in a subgroup with CT evidence offibrosis and in older participants [103]This suggests a generalrole for MUC5B in induction of CT patterns of interstitialpneumonia Such a general observation is likely to be causedby a mechanism that is uniformly present in the human lungThis mechanism might already be identified Mechanicalstress due to respiratory lung movements has been proposedto contribute to IPF and induce such CT patterns [104]

Mathematical modelling showed that the distribution ofIPF lesions on HRCT coincides with the hypothetical distri-bution of maximal mechanical stress [105]We postulate thatin lung where MUC5B is abundantly expressed increasedadmixture of airway fluid to alveolar surfactant fluid mightoccur thereby increasing MUC5B levels in surfactant fluidThe high MUC5B levels in the surfactant fluid might causea significant change in its surface tension lowering capacityOptimal surfactant reduces the surface tension by a factorof about 15 [106] which is necessary for proper alveolar sizeregulation during inspiration and expirationWe hypothesizethat a suboptimal surfactant mix is most abundant anddetrimental at areas with maximal mechanical stress as


Airway epithelium

AEC type I

Capillary

Admixture of alveolar and bronchiolar surfactant

AEC type II

Alveolar surfactant

Claraclub cell

Submucosal gland

MUC5Bproduction

Increased stress on alveolar wall

Fibrogenesis

AEC type II telomereshortening senescence

Suboptimal surfactant fluid

Decreased ability to inflate

Alveolar damage high AEC type II turnover

Figure 1 Hypothesized scheme of increased mechanical stress inMUC5B risk allele carriers At areas with maximal mechanical stress in thelung optimal surface tension lowering capacity of alveolar surfactant fluid is required Through breathing mechanics admixture of alveolarand airway surfactant occurs Increased amounts of MUC5B protein inMUC5B risk allele carriers have detrimental effect on surface tensionlowering capacity of the alveolar surfactant fluid In case of suboptimal surfactant inflation requires increased traction on the alveolar walland induces epithelial damage Alveolar repair causes high epithelial cell turnover with consequent critical shortening of telomeres which inturn induce senescence of alveolar epithelial type II cells

the surface tension lowering capacity of alveolar surfactantfluid is most important in these areas Increased mechanicalstress causes alveolar damage that will initially be repaired byAEC type II Increased turnover of AEC type II is associatedwith decreased telomere length which in turn will lead toAEC type II senescence (Figure 1) Further experiments arenecessary to confirm this hypothesis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] G Raghu H R Collard J J Egan et al ldquoAn officialATSERSJRSALAT statement idiopathic pulmonary fibrosisevidence-based guidelines for diagnosis and managementrdquoAmerican Journal of Respiratory and Critical Care Medicine vol183 no 6 pp 788ndash824 2011

[2] T M Maher A U Wells and G J Laurent ldquoIdiopathicpulmonary fibrosismultiple causes andmultiplemechanismsrdquoEuropean Respiratory Journal vol 30 no 5 pp 835ndash839 2007

[3] M P Steele M C Speer J E Loyd et al ldquoClinical andpathologic features of familial interstitial pneumoniardquo Ameri-can Journal of Respiratory and Critical Care Medicine vol 172no 9 pp 1146ndash1152 2005

[4] WD Travis U Costabel DMHansell et al ldquoAn official Amer-icanThoracic SocietyEuropean Respiratory Society statement

update of the international multidisciplinary classification ofthe idiopathic interstitial pneumoniasrdquo American Journal ofRespiratory and Critical Care Medicine vol 188 no 6 pp 733ndash748 2013

[5] J J Swigris A L Olson T J Huie et al ldquoEthnic and racialdifferences in the presence of idiopathic pulmonary fibrosis atdeathrdquo Respiratory Medicine vol 106 no 4 pp 588ndash593 2012

[6] LM Young R Hopkins andM LWilsher ldquoLower occurrenceof idiopathic pulmonary fibrosis inmaori and pacific islandersrdquoRespirology vol 11 no 4 pp 467ndash470 2006

[7] P P Bonanni J W Frymoyer and R F Jacox ldquoA family studyof idiopathic pulmonary fibrosis A possible dysproteinemicand genetically determined diseaserdquo The American Journal ofMedicine vol 39 no 3 pp 411ndash421 1965

[8] P Swaye H S Van Ordstrand L J McCormack and S EWolpaw ldquoFamilial hamman-rich syndrome Report of eightcasesrdquo Chest vol 55 no 1 pp 7ndash12 1969

[9] M Schou A Amdisen S Eskjaer Jensen and T OlsenldquoOccurrence of goitre during lithium treatmentrdquo The BritishMedical Journal vol 3 no 5620 pp 710ndash713 1968

[10] C H M van Moorsel M F M van Oosterhout N P Barlo etal ldquoSurfactant protein Cmutations are the basis of a significantportion of adult familial pulmonary fibrosis in a dutch cohortrdquoAmerican Journal of Respiratory and Critical Care Medicine vol182 no 11 pp 1419ndash1425 2010

[11] J E Loyd ldquoPulmonary fibrosis in familiesrdquo American Journalof Respiratory Cell and Molecular Biology vol 29 no 3supplement pp S47ndashS50 2003

[12] C Garcıa-Sancho I Buendıa-Roldan M R Fernandez-Plata etal ldquoFamilial pulmonary fibrosis is the strongest risk factor for


idiopathic pulmonary fibrosisrdquo Respiratory Medicine vol 105no 12 pp 1902ndash1907 2011

[13] M B Scholand H Coon R Wolff and L Cannon-AlbrightldquoUse of a genealogical database demonstrates heritability ofpulmonary fibrosisrdquo Lung vol 191 no 5 pp 475ndash481 2013

[14] L M Nogee A E Dunbar S E Wert F Askin A Hamvasand J A Whitsett ldquoA mutation in the surfactant protein Cgene associated with familial interstitial lung diseaserdquoThe NewEngland Journal of Medicine vol 344 no 8 pp 573ndash579 2001

[15] S Ono T Tanaka M Ishida et al ldquoSurfactant protein CG100S mutation causes familial pulmonary fibrosis in Japanesekindredrdquo European Respiratory Journal vol 38 no 4 pp 861ndash869 2011

[16] A Q Thomas K Lane J Phillips III et al ldquoHeterozygosityfor a surfactant protein C gene mutation associated with usualinterstitial pneumonitis and cellular nonspecific interstitialpneumonitis in one kindredrdquo American Journal of Respiratoryand Critical Care Medicine vol 165 no 9 pp 1322ndash1328 2002

[17] W E Lawson S W Grant V Ambrosini et al ldquoGeneticmutations in surfactant protein C are a rare cause of sporadiccases of IPFrdquoThorax vol 59 no 11 pp 977ndash980 2004

[18] P Markart C Ruppert M Wygrecka et al ldquoSurfactant proteinC mutations in sporadic forms of idiopathic interstitial pneu-moniasrdquoEuropeanRespiratory Journal vol 29 no 1 pp 134ndash1372007

[19] A Hamvas L M Nogee F V White et al ldquoProgressive lungdisease and surfactant dysfunction with a deletion in surfactantprotein C generdquo American Journal of Respiratory Cell andMolecular Biology vol 30 no 6 pp 771ndash776 2004

[20] S Mulugeta J M Gray K L Notarfrancesco et al ldquoIdentifica-tion of LBM180 a lamellar body limiting membrane protein ofalveolar type II cells as the ABC transporter protein ABCA3rdquoThe Journal of Biological Chemistry vol 277 no 25 pp 22147ndash22155 2002

[21] M F Beers and S Mulugeta ldquoSurfactant protein C biosynthesisand its emerging role in conformational lung diseaserdquo AnnualReview of Physiology vol 67 pp 663ndash696 2005

[22] J A Kropski W E Lawson L R Young and T S BlackwellldquoGenetic studies provide clues on the pathogenesis of idiopathicpulmonary fibrosisrdquoDiseaseModels andMechanisms vol 6 no1 pp 9ndash17 2013

[23] W E Lawson P F Crossno V V Polosukhin et al ldquoEndoplas-mic reticulum stress in alveolar epithelial cells is prominent inIPF association with altered surfactant protein processing andherpesvirus infectionrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 6 pp L1119ndashL1126 2008

[24] H Tanjore D-S Cheng A L Degryse et al ldquoAlveolar epithelialcells undergo epithelial-to-mesenchymal transition in responseto endoplasmic reticulum stressrdquo The Journal of BiologicalChemistry vol 286 no 35 pp 30972ndash30980 2011

[25] S Mulugeta J A Maguire J L Newitt S J Russo AKotorashvili and M F Beers ldquoMisfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- andcytochrome c-related mechanismsrdquo The American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 293no 3 pp L720ndashL729 2007

[26] B D Uhal and H Nguyen ldquoThe witschi hypothesis revisitedafter 35 years genetic proof from SP-C BRICHOS domainmutationsrdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 305 no 12 pp L906ndashL911 2013

[27] M Korfei C Ruppert P Mahavadi et al ldquoEpithelial endoplas-mic reticulum stress and apoptosis in sporadic idiopathic pul-monary fibrosisrdquo American Journal of Respiratory and CriticalCare Medicine vol 178 no 8 pp 838ndash846 2008

[28] H S Cameron M Somaschini P Carrera et al ldquoA commonmutation in the surfactant protein C gene associated with lungdiseaserdquo The Journal of Pediatrics vol 146 no 3 pp 370ndash3752005

[29] M F Beers A Hawkins J A Maguire et al ldquoA nonaggregatingsurfactant protein C mutant is misdirected to early endosomesand disrupts phospholipid recyclingrdquo Traffic vol 12 no 9 pp1196ndash1210 2011

[30] A Hawkins S H Guttentag R Deterding et al ldquoA non-BRICHOS SFTPCmutant (SP-CI73T) linked to interstitial lungdisease promotes a late block in macroautophagy disrupt-ing cellular proteostasis and mitophagyrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 308no 1 pp L33ndashL47 2015

[31] M Woischnik C Sparr S Kern et al ldquoA non-BRICHOSsurfactant protein c mutation disrupts epithelial cell functionand intercellular signalingrdquo BMC Cell Biology vol 11 article 882010

[32] YWang P J Kuan C Xing et al ldquoGenetic defects in surfactantprotein A2 are associated with pulmonary fibrosis and lungcancerrdquo American Journal of Human Genetics vol 84 no 1 pp52ndash59 2009

[33] J Madsen I Tornoslashe O Nielsen C Koch W Steinhilber andU Holmskov ldquoExpression and localization of lung surfactantprotein A in human tissuesrdquo American Journal of RespiratoryCell and Molecular Biology vol 29 no 5 pp 591ndash597 2003

[34] J Floros G Wang and A N Mikerov ldquoGenetic complexity ofthe human innate host defense molecules surfactant proteinA1 (SP-A1) and SP-A2mdashimpact on functionrdquo Critical Reviewsin Eukaryotic Gene Expression vol 19 no 2 pp 125ndash137 2009

[35] M Maitra Y Wang R D Gerard C R Mendelson and CK Garcia ldquoSurfactant protein A2 mutations associated withpulmonary fibrosis lead to protein instability and endoplasmicreticulum stressrdquo The Journal of Biological Chemistry vol 285no 29 pp 22103ndash22113 2010

[36] B Zhu C H Ferry L K Markell et al ldquoThe nuclear receptorperoxisome proliferator-activated receptor-120573120575 (PPAR120573120575)promotes oncogene-induced cellular senescence throughrepression of endoplasmic reticulum stressrdquo Journal ofBiological Chemistry vol 289 no 29 pp 20102ndash20119 2014

[37] S A YousemandMB Beasley ldquoBronchioloalveolar carcinomaa review of current concepts and evolving issuesrdquo Archives ofPathology and LaboratoryMedicine vol 131 no 7 pp 1027ndash10322007

[38] S Shulenin L M Nogee T Annilo S E Wert J A Whitsettand M Dean ldquoABCA3 gene mutations in newborns with fatalsurfactant deficiencyrdquoTheNewEngland Journal ofMedicine vol350 no 13 pp 1296ndash1303 2004

[39] F Flamein L Riffault C Muselet-Charlier et al ldquoMolecularand cellular characteristics of ABCA3 mutations associatedwith diffuse parenchymal lung diseases in childrenrdquo HumanMolecular Genetics vol 21 no 4 pp 765ndash775 2012

[40] G H Deutsch L R Young R R Deterding et al ldquoDiffuse lungdisease in young children application of a novel classificationschemerdquo American Journal of Respiratory and Critical CareMedicine vol 176 no 11 pp 1120ndash1128 2007


[41] N Cheong M Madesh L W Gonzales et al ldquoFunctional andtrafficking defects in ATP binding cassette A

3mutants associ-

ated with respiratory distress syndromerdquo Journal of BiologicalChemistry vol 281 no 14 pp 9791ndash9800 2006

[42] Y Matsumura N Ban K Ueda and N Inagaki ldquoCharacter-ization and classification of ATP-binding cassette transporterABCA3 mutants in fatal surfactant deficiencyrdquo Journal ofBiological Chemistry vol 281 no 45 pp 34503ndash34514 2006

[43] Y Matsumura N Ban and N Inagaki ldquoAberrant catalyticcycle and impaired lipid transport into intracellular vesicles inABCA3 mutants associated with nonfatal pediatric interstitiallung diseaserdquoTheAmerican Journal of Physiology Lung Cellularand Molecular Physiology vol 295 no 4 pp L698ndashL707 2008

[44] N Weichert E Kaltenborn A Hector et al ldquoSome ABCA3mutations elevate ER stress and initiate apoptosis of lungepithelial cellsrdquo Respiratory Research vol 12 article 4 2011

[45] I Campo M Zorzetto F Mariani et al ldquoA large kindredof pulmonary fibrosis associated with a novel ABCA3 genevariantrdquo Respiratory Research vol 15 article 43 2014

[46] R Epaud C Delestrain M Louha S Simon P Fanen andA Tazi ldquoCombined pulmonary fibrosis and emphysema syn-drome associated with ABCA3 mutationsrdquo European Respira-tory Journal vol 43 no 2 pp 638ndash641 2014

[47] V Cottin H Nunes P-Y Brillet et al ldquoCombined pulmonaryfibrosis and emphysema a distinct underrecognised entityrdquoEuropean Respiratory Journal vol 26 no 4 pp 586ndash593 2005

[48] M Brantly N A Avila V Shotelersuk C Lucero M Huizingand W A Gahl ldquoPulmonary function and high-resolutionCT findings in patients with an inherited form of pulmonaryfibrosis Hermansky-Pudlak syndrome due to mutations inHPS-1rdquo Chest vol 117 no 1 pp 129ndash136 2000

[49] C Carmona-Rivera D R Simeonov N D Cardillo W AGahl and C L Cadilla ldquoA divalent interaction between HPS1and HPS4 is required for the formation of the biogenesis oflysosome-related organelle complex-3 (BLOC-3)rdquoBiochimica etBiophysica Acta vol 1833 no 3 pp 468ndash478 2013

[50] S M Casalino-Matsuda M E Monzon A J Day and RM Forteza ldquoHyaluronan fragmentsCD44 mediate oxidativestress-induced MUC5B up-regulation in airway epitheliumrdquoTheAmerican Journal of Respiratory Cell andMolecular Biologyvol 40 no 3 pp 277ndash285 2009

[51] A-H Wei and W Li ldquoHermansky-Pudlak syndrome pig-mentary and non-pigmentary defects and their pathogenesisrdquoPigment Cell andMelanoma Research vol 26 no 2 pp 176ndash1922013

[52] D M Pierson D Ionescu G Qing et al ldquoPulmonary fibrosisin Hermansky-Pudlak syndrome a case report and reviewrdquoRespiration vol 73 no 3 pp 382ndash395 2006

[53] K Furuhashi N Enomoto T Fujisawa et al ldquoHermansky-Pudlak syndrome with nonspecific interstitial pneumoniardquoInternal Medicine vol 53 no 5 pp 449ndash453 2014

[54] J J van der Vis L ten Klooster M F M van Oosterhout JC Grutters and C H M van Moorsel ldquoThe occurrence ofhermansky pudlak syndrome in patients with idiopathic pul-monary fibrosismdasha cohort studyrdquo Journal of Genetic Syndromesamp Gene Therapy vol 4 article 141 2013

[55] M Y Armanios J J-L Chen J D Cogan et al ldquoTelomerasemutations in families with idiopathic pulmonary fibrosisrdquo TheNew England Journal of Medicine vol 356 no 13 pp 1317ndash13262007

[56] K D Tsakiri J T Cronkhite P J Kuan et al ldquoAdult-onsetpulmonary fibrosis caused by mutations in telomeraserdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 104 no 18 pp 7552ndash7557 2007

[57] M Armanios ldquoTelomeres and age-related disease how telom-ere biology informs clinical paradigmsrdquoThe Journal of ClinicalInvestigation vol 123 no 3 pp 996ndash1002 2013

[58] A J Zaug S M Crary M J Fioravanti K Campbell and T RCech ldquoMany disease-associated variants of hTERT retain hightelomerase enzymatic activityrdquo Nucleic Acids Research vol 41no 19 pp 8969ndash8978 2013

[59] T Vulliamy A Marrone R Szydlo A Walne P J Mason andI Dokal ldquoDisease anticipation is associated with progressivetelomere shortening in families with dyskeratosis congenita dueto mutations in TERCrdquo Nature Genetics vol 36 no 5 pp 447ndash449 2004

[60] J T Cronkhite C Xing G Raghu et al ldquoTelomere shorteningin familial and sporadic pulmonary fibrosisrdquo American Journalof Respiratory andCritical CareMedicine vol 178 no 7 pp 729ndash737 2008

[61] J K Alder J J-L Chen L Lancaster et al ldquoShort telomeres area risk factor for idiopathic pulmonary fibrosisrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 105 no 35 pp 13051ndash13056 2008

[62] R Snetselaar C H van Moorsel K M Kazemier et alldquoTelomere length in interstitial lung diseasesrdquo Chest 2015

[63] J K Alder S E Stanley C L Wagner M Hamilton V SHanumanthu andM Armanios ldquoExome sequencing identifiesmutant TINF2 in a family with pulmonary fibrosisrdquo Chest vol147 no 5 pp 1361ndash1368 2015

[64] J A Kropski D B Mitchell C Markin et al ldquoA noveldyskerin (DKC1)mutation is associated with familial interstitialpneumoniardquo Chest vol 146 no 1 pp e1ndashe7 2014

[65] JDCogan J AKropskiM Zhao et al ldquoRare variants inRTEL1are associated with familial interstitial pneumoniardquo AmericanJournal of Respiratory and Critical Care Medicine vol 191 no 6pp 646ndash655 2015

[66] C Kannengiesser R Borie C Menard et al ldquoHeterozygousRTEL1 mutations are associated with familial pulmonary fibro-sisrdquo European Respiratory Journal vol 46 no 2 pp 474ndash4852015

[67] B D Stuart J Choi S Zaidi et al ldquoExome sequencing linksmutations in PARNandRTEL1with familial pulmonary fibrosisand telomere shorteningrdquo Nature Genetics vol 47 no 5 pp512ndash517 2015

[68] C E Barkauskas M J Cronce C R Rackley et al ldquoType 2alveolar cells are stem cells in adult lungrdquoThe Journal of ClinicalInvestigation vol 123 no 7 pp 3025ndash3036 2013

[69] D Warburton L Perin R Defilippo S Bellusci W Shi andB Driscoll ldquoStemprogenitor cells in lung development injuryrepair and regenerationrdquo Proceedings of the American ThoracicSociety vol 5 no 6 pp 703ndash706 2008

[70] J K Alder C E Barkauskas N Limjunyawong et al ldquoTelomeredysfunction causes alveolar stem cell failurerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 112 no 16 pp 5099ndash5104 2015

[71] M Plataki A V Koutsopoulos K Darivianaki G Delides NM Siafakas and D Bouros ldquoExpression of apoptotic and anti-apoptotic markers in epithelial cells in idiopathic pulmonaryfibrosisrdquo Chest vol 127 no 1 pp 266ndash274 2005


[72] N M Korthagen C H M van Moorsel N P Barlo K MKazemier H J T Ruven and J C Grutters ldquoAssociationbetween variations in cell cycle genes and idiopathic pulmonaryfibrosisrdquo PLoS ONE vol 7 no 1 Article ID e30442 2012

[73] J C Grutters and R M du Bois ldquoGenetics of fibrosing lungdiseasesrdquo European Respiratory Journal vol 25 no 5 pp 915ndash927 2005

[74] N P Barlo C H M van Moorsel N M Korthagen et alldquoGenetic variability in the IL1RN gene and the balance betweeninterleukin (IL)-1 receptor agonist and IL-1beta in idiopathicpulmonary fibrosisrdquo Clinical and Experimental Immunologyvol 166 no 3 pp 346ndash351 2011

[75] R L Riha I A Yang G C Rabnott A M Tunnicliffe K MFong and P V Zimmerman ldquoCytokine gene polymorphisms inidiopathic pulmonary fibrosisrdquo Internal Medicine Journal vol34 no 3 pp 126ndash129 2004

[76] M Whyte R Hubbard R Meliconi et al ldquoIncreased riskof fibrosing alveolitis associated with interleukin-1 receptorantagonist and tumor necrosis factor-120572 gene polymorphismsrdquoTheAmerican Journal of Respiratory and Critical Care Medicinevol 162 no 2 pp 755ndash758 2000

[77] B Hutyrova P Pantelidis J Drabek et al ldquoInterleukin-1gene cluster polymorphisms in sarcoidosis and idiopathic pul-monary fibrosisrdquo American Journal of Respiratory and CriticalCare Medicine vol 165 no 2 pp 148ndash151 2002

[78] N M Korthagen C H M van Moorsel K M KazemierH J T Ruven and J C Grutters ldquoIL1RN genetic variationsand risk of IPF a meta-analysis and mRNA expression studyrdquoImmunogenetics vol 64 no 5 pp 371ndash377 2012

[79] PGasse CMary I Guenon et al ldquoIL-1R1MyD88 signaling andthe inflammasome are essential in pulmonary inflammationand fibrosis in micerdquo The Journal of Clinical Investigation vol117 no 12 pp 3786ndash3799 2007

[80] I Aksentijevich S L Masters P J Ferguson et al ldquoAnautoinflammatory disease with deficiency of the interleukin-1-receptor antagonistrdquoThe New England Journal of Medicine vol360 no 23 pp 2426ndash2437 2009

[81] E Arzt J Sauer T Pollmacher et al ldquoGlucocorticoids suppressinterleukin-1 receptor antagonist synthesis following inductionby endotoxinrdquo Endocrinology vol 134 no 2 pp 672ndash677 1994

[82] G Raghu K J Anstrom T E King Jr J A Lasky and F JMartinez ldquoPrednisone azathioprine and N-acetylcysteine forpulmonary fibrosisrdquoThe New England Journal of Medicine vol366 no 21 pp 1968ndash1977 2012

[83] M A Seibold A L Wise M C Speer et al ldquoA commonMUC5B promoter polymorphism and pulmonary fibrosisrdquoTheNew England Journal of Medicine vol 364 no 16 pp 1503ndash15122011

[84] Y Zhang I Noth J G N Garcia and N Kaminski ldquoA variantin the promoter of MUC5B and idiopathic pulmonary fibrosisrdquoTheNew England Journal of Medicine vol 364 no 16 pp 1576ndash1577 2011

[85] W Bodmer and C Bonilla ldquoCommon and rare variants in mul-tifactorial susceptibility to common diseasesrdquo Nature Geneticsvol 40 no 6 pp 695ndash701 2008

[86] A L Peljto M Selman D S Kim et al ldquoTheMUC5B promoterpolymorphism is associated with idiopathic pulmonary fibrosisin a Mexican cohort but is rare among Asian ancestriesrdquo Chestvol 147 no 2 pp 460ndash464 2015

[87] Y Horimasu S Ohshimo F Bonella et al ldquoMUC5B promoterpolymorphism in Japanese patients with idiopathic pulmonaryfibrosisrdquo Respirology vol 20 no 3 pp 439ndash444 2015

[88] M A Seibold R W Smith C Urbanek et al ldquoThe idiopathicpulmonary fibrosis honeycomb cyst contains a mucocilarypseudostratified epitheliumrdquo PLoS ONE vol 8 no 3 Article IDe58658 2013

[89] Y Chen Y H Zhao Y-P Di and R Wu ldquoCharacterization ofhuman mucin 5B gene expression in airway epithelium and thegenomic clone of the amino-terminal and 51015840-flanking regionrdquoAmerican Journal of Respiratory Cell andMolecular Biology vol25 no 5 pp 542ndash553 2001

[90] M C Rose and J A Voynow ldquoRespiratory tract mucin genesand mucin glycoproteins in health and diseaserdquo PhysiologicalReviews vol 86 no 1 pp 245ndash278 2006

[91] T Fujisawa M M-J Chang S Velichko et al ldquoNF-120581B medi-ates IL-1120573- and IL-17A-induced MUC5B expression in airwayepithelial cellsrdquo The American Journal of Respiratory Cell andMolecular Biology vol 45 no 2 pp 246ndash252 2011

[92] G P Cosgrove S D Groshong A L Peljto et al ldquoTheMUC5Bpromoter polymorphism is associated with a less severe patho-logical form of familial interstitial pneumonia (FIP)rdquo AmericanJournal of Respiratory and Critical Care Medicine vol 185Article ID A6865 2012

[93] M G Roy A Livraghi-Butrico A A Fletcher et al ldquoMuc5bis required for airway defencerdquo Nature vol 505 no 7483 pp412ndash416 2014

[94] P L Molyneaux M J Cox S A G Willis-Owen et alldquoThe role of bacteria in the pathogenesis and progression ofidiopathic pulmonary fibrosisrdquoAmerican Journal of Respiratoryand Critical Care Medicine vol 190 no 8 pp 906ndash913 2014

[95] A L Peljto Y Zhang T E Fingerlin et al ldquoAssociation betweenthe MUC5B promoter polymorphism and survival in patientswith idiopathic pulmonary fibrosisrdquo Journal of the AmericanMedical Association vol 309 no 21 pp 2232ndash2239 2013

[96] C J Stock H Sato C Fonseca et al ldquoMucin 5B promoterpolymorphism is associated with idiopathic pulmonary fibrosisbut not with development of lung fibrosis in systemic sclerosisor sarcoidosisrdquoThorax vol 68 no 5 pp 436ndash441 2013

[97] T Mushiroda S Wattanapokayakit A Takahashi et al ldquoAgenome-wide association study identifies an association of acommon variant in TERT with susceptibility to idiopathicpulmonary fibrosisrdquo Journal of Medical Genetics vol 45 no 10pp 654ndash656 2008

[98] T E Fingerlin E Murphy W Zhang et al ldquoGenome-wideassociation study identifies multiple susceptibility loci for pul-monary fibrosisrdquo Nature Genetics vol 45 no 6 pp 613ndash6202013

[99] HCorvol C AHodgesM LDrumm andLGuillot ldquoMovingbeyond genetics is FAM13A a major biological contributor inlung physiology and chronic lung diseasesrdquo Journal of MedicalGenetics vol 51 no 10 pp 646ndash649 2014

[100] I Noth Y Zhang S-F Ma et al ldquoGenetic variants associatedwith idiopathic pulmonary fibrosis susceptibility and mortal-ity a genome-wide association studyrdquo The Lancet RespiratoryMedicine vol 1 no 4 pp 309ndash317 2013

[101] D E Reich M Cargili S Boik et al ldquoLinkage disequilibriumin the human genomerdquo Nature vol 411 no 6834 pp 199ndash2042001

[102] W Y S Wang B J Barratt D G Clayton and J A ToddldquoGenome-wide association studies theoretical and practicalconcernsrdquo Nature Reviews Genetics vol 6 no 2 pp 109ndash1182005

[103] G M Hunninghake H Hatabu Y Okajima et al ldquoMUC5Bpromoter polymorphism and interstitial lung abnormalitiesrdquo


TheNew England Journal of Medicine vol 368 no 23 pp 2192ndash2200 2013

[104] K O Leslie ldquoIdiopathic pulmonary fibrosis may be a disease ofrecurrent tractional injury to the periphery of the aging lunga unifying hypothesis regarding etiology and pathogenesisrdquoArchives of Pathology and Laboratory Medicine vol 136 no 6pp 591ndash600 2012

[105] A Carloni V Poletti L Fermo N Bellomo and M ChilosildquoHeterogeneous distribution of mechanical stress in humanlung a mathematical approach to evaluate abnormal remodel-ing in IPFrdquo Journal of Theoretical Biology vol 332 pp 136ndash1402013

[106] D Shier J Butler and R Lewis ldquoRespiratory systemrdquo inHolersquos Human Anatomy and Physiology chapter 19 pp 752ndash790McGraw-Hill 11th edition 2007

[107] J A Whitsett S E Wert and T E Weaver ldquoAlveolar surfac-tant homeostasis and the pathogenesis of pulmonary diseaserdquoAnnual Review of Medicine vol 61 pp 105ndash119 2010

[108] R Zarbock M Woischnik C Sparr et al ldquoThe surfactantproteinCmutationA116Dalters cellular processing stress toler-ance surfactant lipid composition and immune cell activationrdquoBMC Pulmonary Medicine vol 12 article 15 2012

[109] J A Maguire S Mulugeta and M F Beers ldquoEndoplasmicreticulum stress induced by surfactant protein C BRICHOSmutants promotes proinflammatory signaling by epithelialcellsrdquo American Journal of Respiratory Cell and MolecularBiology vol 44 no 3 pp 404ndash414 2011

[110] S Mulugeta V Nguyen S J Russo M Muniswamy and MF Beers ldquoA surfactant protein C precursor protein BRICHOSdomain mutation causes endoplasmic reticulum stress protea-some dysfunction and caspase 3 activationrdquo American Journalof Respiratory Cell and Molecular Biology vol 32 no 6 pp 521ndash530 2005

[111] J A Maguire S Mulugeta and M F Beers ldquoMultiple ways todie delineation of the unfolded protein response and apoptosisinduced by surfactant protein C BRICHOS mutantsrdquo Interna-tional Journal of Biochemistry and Cell Biology vol 44 no 1 pp101ndash112 2012

[112] T Thurm E Kaltenborn S Kern M Griese and R ZarbockldquoSFTPC mutations cause SP-C degradation and aggregateformation without increasing ER stressrdquo European Journal ofClinical Investigation vol 43 no 8 pp 791ndash800 2013

[113] K R Khubchandani K L Goss J F Engelhardt and JM Snyder ldquoIn situ hybridization of SP-A mRNA in adulthuman conducting airwaysrdquo Pediatric Pathology and MolecularMedicine vol 20 no 5 pp 349ndash366 2001

[114] H Saitoh H Okayama S Shimura T Fushimi T Masuda andK Shirato ldquoSurfactant protein A2 gene expression by humanairway submucosal gland cellsrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 19 no 2 pp 202ndash209 1998

[115] M J Tino and J R Wright ldquoInteractions of surfactant proteinAwith epithelial cells and phagocytesrdquo Biochimica et BiophysicaActamdashMolecular Basis of Disease vol 1408 no 2-3 pp 241ndash2631998

[116] C JWong J Akiyama L Allen and S Hawgood ldquoLocalizationand developmental expression of surfactant proteins D andA inthe respiratory tract of the mouserdquo Pediatric Research vol 39no 6 pp 930ndash937 1996

[117] A M Pastva J R Wright and K L Williams ldquoImmunomodu-latory roles of surfactant proteins A and D implications in lungdiseaserdquo Proceedings of the AmericanThoracic Society vol 4 no3 pp 252ndash257 2007

[118] YWang P J Kuan C Xing et al ldquoGenetic defects in surfactantprotein A2 are associated with pulmonary fibrosis and lungcancerrdquo The American Journal of Human Genetics vol 84 no1 pp 52ndash59 2009

[119] Y Song G Fang H Shen et al ldquoHuman surfactant proteinA2 gene mutations impair dimmertrimer assembly leading todeficiency in protein sialylation and secretionrdquo PLoS ONE vol7 no 10 Article ID e46559 2012

[120] G Yamano H Funahashi O Kawanami et al ldquoABCA3 is alamellar body membrane protein in human lung alveolar typeII cellsrdquo FEBS Letters vol 508 no 2 pp 221ndash225 2001

[121] E Bruder J Hofmeister C Aslanidis et al ldquoUltrastructuraland molecular analysis in fatal neonatal interstitial pneumoniacaused by a novel ABCA3mutationrdquoModern Pathology vol 20no 10 pp 1009ndash1018 2007

[122] T H Garmany M A Moxley F V White et al ldquoSurfactantcomposition and function in patients with ABCA3 mutationsrdquoPediatric Research vol 59 no 6 pp 801ndash805 2006

[123] B Driscoll S Buckley K C Bui K D Anderson and DWarburton ldquoTelomerase in alveolar epithelial development andrepairrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 279 no 6 pp L1191ndashL1198 2000

[124] T Liu M Ullenbruch Y Y Choi et al ldquoTelomerase andtelomere length in pulmonary fibrosisrdquo American Journal ofRespiratory Cell and Molecular Biology vol 49 no 2 pp 260ndash268 2013

[125] Y Nozaki T Liu K Hatano M Gharaee-Kermani and SH Phan ldquoInduction of telomerase activity in fibroblasts frombleomycin-injured lungsrdquo American Journal of Respiratory Celland Molecular Biology vol 23 no 4 pp 460ndash465 2000

[126] Z G Fridlender P Y Cohen O Golan N Arish S Wallach-Dayan and R Breuer ldquoTelomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosisrdquo EuropeanRespiratory Journal vol 30 no 2 pp 205ndash213 2007

[127] C W Greider and E H Blackburn ldquoIdentification of a specifictelomere terminal transferase activity in tetrahymena extractsrdquoCell vol 43 no 2 part 1 pp 405ndash413 1985

[128] J-L Chen and C W Greider ldquoTelomerase RNA structure andfunction implications for dyskeratosis congenitardquo Trends inBiochemical Sciences vol 29 no 4 pp 183ndash192 2004

[129] C W Greider and E H Blackburn ldquoThe telomere terminaltransferase of tetrahymena is a ribonucleoprotein enzyme withtwo kinds of primer specificityrdquo Cell vol 51 no 6 pp 887ndash8981987

[130] CWGreider and EH Blackburn ldquoA telomeric sequence in theRNA of Tetrahymena telomerase required for telomere repeatsynthesisrdquo Nature vol 337 no 6205 pp 331ndash337 1989

[131] A Diaz de Leon J T Cronkhite A-L A Katzenstein et alldquoTelomere lengths pulmonary fibrosis and telomerase (TERT)mutationsrdquo PLoS ONE vol 5 no 5 Article ID e10680 2010

[132] J M Gansner I O Rosas and B L Ebert ldquoPulmonaryfibrosis bone marrow failure and telomerase mutationrdquo TheNew England Journal of Medicine vol 366 no 16 pp 1551ndash15532012

[133] E M Parry J K Alder X Qi J J-L Chen and M ArmaniosldquoSyndrome complex of bone marrow failure and pulmonaryfibrosis predicts germline defects in telomeraserdquo Blood vol 117no 21 pp 5607ndash5611 2011

[134] D C Chambers B E Clarke J McGaughran and C K GarcialdquoLung fibrosis premature graying andmacrocytosisrdquoAmericanJournal of Respiratory and Critical CareMedicine vol 186 no 5pp e8ndashe9 2012


[135] R T Calado J A Regal D E Kleiner et al ldquoA spectrumof severe familial liver disorders associate with telomerasemutationsrdquo PLoS ONE vol 4 no 11 Article ID e7926 2009

[136] M Armanios J-L Chen Y-P C Chang et al ldquoHaploinsuffi-ciency of telomerase reverse transcriptase leads to anticipationin autosomal dominant dyskeratosis congenitardquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 102 no 44 pp 15960ndash15964 2005

[137] H-Y Du R Idol S Robledo et al ldquoTelomerase reverse tran-scriptase haploinsufficiency and telomere length in individualswith 5p- syndromerdquo Aging Cell vol 6 no 5 pp 689ndash697 2007

[138] C K Garcia W E Wright and J W Shay ldquoHuman diseasesof telomerase dysfunction insights into tissue agingrdquo NucleicAcids Research vol 35 no 22 pp 7406ndash7416 2007

[139] J K Alder N Guo F Kembou et al ldquoTelomere length is adeterminant of emphysema susceptibilityrdquo American Journal ofRespiratory and Critical Care Medicine vol 184 no 8 pp 904ndash912 2011

[140] S-R Jackson J Lee R Reddy et al ldquoPartial pneumonectomyof telomerase null mice carrying shortened telomeres initiatescell growth arrest resulting in a limited compensatory growthresponserdquo The American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 6 pp L898ndashL909 2011

[141] H Ly M Schertzer W Jastaniah et al ldquoIdentification andfunctional characterization of 2 variant alleles of the telomeraseRNA template gene (TERC) in a patient with dyskeratosiscongenitardquo Blood vol 106 no 4 pp 1246ndash1252 2005

[142] A Marrone P Sokhal A Walne et al ldquoFunctional char-acterization of novel telomerase RNA (TERC) mutations inpatients with diverse clinical and pathological presentationsrdquoHaematologica vol 92 no 8 pp 1013ndash1020 2007

[143] F Goldman R Bouarich S Kulkarni et al ldquoThe effect ofTERChaploinsufficiency on the inheritance of telomere lengthrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 47 pp 17119ndash17124 2005

[144] T Vulliamy A Marrone F Goldman et al ldquoThe RNA compo-nent of telomerase is mutated in autosomal dominant dysker-atosis congenitardquo Nature vol 413 no 6854 pp 432ndash435 2001

[145] N S Heiss S W Knight T J Vulliamy et al ldquoX-linked dysker-atosis congenita is caused by mutations in a highly conservedgene with putative nucleolar functionsrdquoNature Genetics vol 19no 1 pp 32ndash38 1998

[146] J K Alder E M Parry S Yegnasubramanian et al ldquoTelomerephenotypes in females with heterozygous mutations in thedyskeratosis congenita 1 (DKC1) generdquo Human Mutation vol34 no 11 pp 1481ndash1485 2013

[147] W F Safa G G Lestringant and P M Frossard ldquoX-linkeddyskeratosis congenita restrictive pulmonary disease and anovel mutationrdquoThorax vol 56 no 11 pp 891ndash894 2001

[148] S Hisata H Sakaguchi H Kanegane et al ldquoA novel missensemutation of DKC1 in dyskeratosis congenita with pulmonaryfibrosisrdquo Sarcoidosis Vasculitis and Diffuse Lung Diseases vol30 no 3 pp 221ndash225 2013

[149] L A Dvorak R Vassallo S Kirmani et al ldquoPulmonary fibrosisin dyskeratosis congenita report of 2 casesrdquo Human Pathologyvol 46 no 1 pp 147ndash152 2014

[150] S-H Kim P Kaminker and J Campisi ldquoTIN2 a new regulatorof telomere length in human cellsrdquo Nature Genetics vol 23 no4 pp 405ndash412 1999

[151] W Palm and T de Lange ldquoHow shelterin protects mammaliantelomeresrdquo Annual Review of Genetics vol 42 pp 301ndash3342008

[152] A Fukuhara Y Tanino T Ishii et al ldquoPulmonary fibrosis indyskeratosis congenita with TINF2 gene mutationrdquo EuropeanRespiratory Journal vol 42 no 6 pp 1757ndash1759 2013

[153] A J Walne T Vulliamy R Beswick M Kirwan and I DokalldquoTINF2 mutations result in very short telomeres analysis of alarge cohort of patients with dyskeratosis congenita and relatedbonemarrow failure syndromesrdquoBlood vol 112 no 9 pp 3594ndash3600 2008

[154] H Ding M Schertzer X Wu et al ldquoRegulation of murinetelomere length by Rtel an essential gene encoding a helicase-like proteinrdquo Cell vol 117 no 7 pp 873ndash886 2004

[155] Z Du D Zhao Y Zhao S Wang Y Gao and N Li ldquoIden-tification and characterization of bovine regulator of telomerelength elongation helicase gene (RTEL) molecular cloningexpression distribution splice variants and DNA methylationprofilerdquo BMCMolecular Biology vol 8 article 18 2007

[156] J-B Vannier G Sarek and S J Boulton ldquoRTEL1 functions ofa disease-associated helicaserdquo Trends in Cell Biology vol 24 no7 pp 416ndash425 2014

[157] Z Deng G Glousker AMolczan et al ldquoInheritedmutations inthe helicase RTEL1 cause telomere dysfunction and hoyeraal-hreidarsson syndromerdquo Proceedings of the National Academyof Sciences of the United States of America vol 110 no 36 ppE3408ndashE3416 2013

[158] K Buiting C Korner B Ulrich E Wahle and B HorsthemkeldquoThe human gene for the poly(A)-specific ribonuclease (PARN)maps to 16p13 and has a truncated copy in the Prader-WilliAngelman syndrome region on 15q11rarr q13rdquo Cytogeneticsand Cell Genetics vol 87 no 1-2 pp 125ndash131 1999

[159] H Tummala A Walne L Collopy et al ldquoPoly(A)-specificribonuclease deficiency impacts telomere biology and causesdyskeratosis congenitardquo The Journal of Clinical Investigationvol 125 no 5 pp 2151ndash2160 2015

[160] Y A Bochkov K M Hanson S Keles R A Brockman-Schneider N N Jarjour and J E Gern ldquoRhinovirus-inducedmodulation of gene expression in bronchial epithelial cells fromsubjectswith asthmardquoMucosal Immunology vol 3 no 1 pp 69ndash80 2010

[161] L-H Pan H Ohtani K Yamauchi and H Nagura ldquoCo-expression of TNF120572 and IL-1120573 in human acute pulmonaryfibrotic diseases an immunohistochemical analysisrdquo PathologyInternational vol 46 no 2 pp 91ndash99 1996

[162] L LiuAA Roberts andTGanz ldquoBy IL-1 signalingmonocyte-derived cells dramatically enhance the epidermal antimicrobialresponse to lipopolysacchariderdquo The Journal of Immunologyvol 170 no 1 pp 575ndash580 2003

[163] S Perrier F Darakhshan and E Hajduch ldquoIL-1 receptorantagonist in metabolic diseases Dr Jekyll or Mr Hyderdquo FEBSLetters vol 580 no 27 pp 6289ndash6294 2006

[164] R Wei C Li M Zhang et al ldquoAssociation between MUC5Band TERT polymorphisms and different interstitial lung diseasephenotypesrdquoTranslational Research vol 163 no 5 pp 494ndash5022014

[165] D J Thornton K Rousseau and M A McGuckin ldquoStructureand function of the polymeric mucins in airways mucusrdquoAnnual Review of Physiology vol 70 pp 459ndash486 2008

[166] R Sepper K Prikk M Metsis et al ldquoMucin5B expression bylung alveolar macrophages is increased in long-term smokersrdquoJournal of Leukocyte Biology vol 92 no 2 pp 319ndash324 2012

[167] R Borie B Crestani P Dieude et al ldquoThe MUC5B variantis associated with idiopathic pulmonary fibrosis but not with


systemic sclerosis interstitial lung disease in the europeancaucasian populationrdquo PLoS ONE vol 8 no 8 Article IDe70621 2013

[168] J A Kropski J M Pritchett D F Zoz et al ldquoExtensive pheno-typing of individuals at risk for familial interstitial pneumoniareveals clues to the pathogenesis of interstitial lung diseaserdquoAmerican Journal of Respiratory and Critical Care Medicine vol191 no 4 pp 417ndash426 2015

[169] M A Coghlan A Shifren H J Huang et al ldquoSequencing ofidiopathic pulmonary fibrosis-related genes reveals indepen-dent single gene associationsrdquo BMJ Open Respiratory Researchvol 1 no 1 Article ID e000057 2014

[170] S Luhrig I Siamishi M Tesmer-Wolf U Zechner W Engeland J Nolte ldquoLrrc34 a novel nucleolar protein interacts withNpm1 and Ncl and has an impact on pluripotent stem cellsrdquoStemCells andDevelopment vol 23 no 23 pp 2862ndash2874 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


include higher occurrence in Hispanics than in Whites andthe lowest occurrence in Blacks and Maori [5 6] In theoryfamilial occurrence may well be explained by presence ofa common environmental cause An environmental causerequires clustering of affected family members in spaceand time while a genetic cause allows for differences inspace and time Such differences are frequently observed infamilial IIP including sibs from different environments andparent-offspring disease with an interval of decades [3 7ndash9] and support the involvement of heritable factors IIP isfamilial in approximately 10 of cases [10] and might evenreach 20 in cohorts with IPF or end-stage lung disease[11 12] These numbers may even be an underestimationbecause the studies relied on patient reports With moreelaborate measurement of familial disease an even largerfamilial component can be identified Scholand and cowork-ers performed an extraordinary study for which they firstidentified 1000 cases that died from pulmonary fibrosis inthe Utah Population Database They showed that the averagerelatedness of these 1000 cases was significantly higher thanthat of matched controls even when first- and second-degreerelatives were excluded [13]

3 Alveolar Epithelial Type II Cell

A major breakthrough was achieved when the first causativemutation was identified in a family with IIP Candidategene sequencing detected a heterozygous mutation in surfac-tant protein C (SFTPC) [14] Because SFTPC is exclusivelyexpressed in type II alveolar epithelial cells (AECs) it wasproof that erroneous processes in AEC type II could ulti-mately lead to pulmonary fibrosis

The reported family already contained many featuresof disease associated with SFTPC mutations familial ILDdominant expression variable penetrance and expressivityresulting in acute and chronic lung disease in individualsranging from newborn to adult [10 15 16] Since the firstdiscovery many IIP families with surfactant mutations havenow been described SFTPC mutations are now establishedas an important cause of paediatric ILD but also known tocontribute to predominantly familial IIP in adults [10 17ndash19] Table 1 summarizes characteristics of mutated genes inIIP and biological consequences of mutations

4 Surfactant Processing

After transcription and translation of SFTPC in AEC type IIa proprotein is formed which after subsequent folding andcleavage steps becomes a mature surfactant protein readyfor secretion into the alveolar space via lamellar bodiesPulmonary surfactant consists of a mixture of lipids andspecific proteins that lowers alveolar surface tension therebypreventing alveolar collapse at the end of expiration [20 21]

Erroneous SFTPC processing is currently one of the beststudied mechanisms leading to IIP The consequence of amutation in SFTPC depends on its position in the gene [22]

Mutations in the C-terminal BRICHOS domain generallyincrease endoplasmic reticulum (ER) stress and activate theunfolded protein response (UPR) in AEC type II [23ndash26]

In turn ER stress can induce epithelial-to-mesenchymaltransition in lung epithelial cells [24]

The role of ER stress is not limited to SFTPC mutationcarriers as different studies showed that AECs in fibrotictissue from nonmutated FIP and sporadic IPF patients werealso positive for ER-stress markers [23 27]

The most common SFTPC mutation is I73T and doesnot cause substantial elevation of ER stress [28] It repre-sents a linker domain mutation that alters trafficking of thepropeptide to early endosomes [29] and causes dysregulatedproteostasis [30] Furthermore alteration of the surfactantlipid composition and activation of immune cells are reportedfor these mutations [31]

Later mutations in a second surfactant associated genesurfactant protein A2 (SFTPA2) were identified in twofamilies Family members presented with adult early-onsetpulmonary fibrosis or lung cancer with features of bronchi-oloalveolar carcinoma [32] Surfactant protein A2 is a C-typelectin important in the defense against respiratory pathogensand in the lung It is expressed not only by AEC type IIbut also by Clara cells and submucosal glands [33 34] Themutant protein when expressed in AECs was not excretedbut retained in the ER and induced ER stress [35] a processsimilar to that seen in SFTPC mutants However there areno reports on lung cancer in patients with SFTPC mutationER stress is linked to tumorigenesis [36] and tumorigenesisin BAC is often thought to involve Clara cells [37]

5 Lamellar Bodies

Lamellar bodies are secretory organelles unique to type IIAECand are crucial for biosynthetic processing and transportof pulmonary surfactant Proteins of the limiting membraneof lamellar bodies are encoded by the gene ABCA3 In thelung the highest expression of ABCA3 has been observed intype II AEC and corresponds with the presence of lamellarbodies [20] Recessive mutations in ABCA3 are the mostcommon genetic cause of lethal surfactant deficiency inneonates or chronic ILD in children [38ndash40]

In type II AECs ABCA3 mutations cause abnormal pro-cessing trafficking and functionality of the ABCA3 protein[41 42] resulting in impaired lipid transport [43] or retentionin the ER compartment and elevated ER stress and apoptoticsignaling [44] Only recently were compound heterozygousor homozygous mutations in ABCA3 described in adult IIP[45 46] A French patient with ABCA3 mutations presentedwith combined pulmonary fibrosis and emphysema (CPFE)[46] CPFE typically occurs inmale smokers but also has sim-ilarities to radiographs of IIP patients with SFTPCmutations[47] Dysfunctional lamellar bodies in AEC type II were alsoidentified as a cause of pulmonary fibrosis in Hermansky-Pudlak Syndrome (HPS)

HPS is a systemic disorder characterized by reducedpigmentation of skin hair and eyes and bleeding diathesisDisease is caused by autosomal recessive mutations in thegene HPS1 [48] that lead to giant lamellar bodies in type IIAECs with a deficiency to fuse with the outer cell membraneand excrete lamellar body content [49ndash51] Pulmonary fibro-sis in HPS shares many similarities with that observed in IPF


Table1Mutated

genesinIIPexpressin

gpu

lmon

arycellsfun

ction

andmutationalcon

sequ

ences

Gene

Expressin

gcells

inlung

Genefun

ctionlowast

Mutated

domain

Effecto

fmutation

Pathologicalprocess

SFTP

CAEC

type

II[107]

Com

ponent

ofsurfa

ctant

fluid

Lower

surfa

cetension[107]

Link

erdo

mainassociates

with

LB[31]

Toxicg

ainof

functio

n[107]

Alteratio

nof

traffi

cking

dysregulationof

proteosta

sis[31]

Alteratio

nof

surfa

ctantlipid

compo

sition[31]

C-term

inalBR

ICHOS

domainfolded

inER

and

GA[108]

ERstr

essa

ndUPR

upregu

latio

n[109ndash111]

Activ

ationof

immun

ecells[112]

Alteratio

nof

surfa

ctantlipid

compo

sition[112]

SFTP

A2

AEC

type

IIClaraclu

bcell

Subm

ucosalgland

[113ndash116]

Collectin

(tomod

ulate

innateandadaptiv

eim

mun

ity)[107117

]

Carboh

ydrate-recognitio

ndo

main[32]

Toxicg

ainof

functio

n[118]

Increase

ofER

stress[118

]UPR

upregu

latio

n[35119

]

ABCA

3AEC

type

II[120]

Limiting

mem

branep

rotein

oflamellarb

ody[107]

Intracellularloo

pextracellulard

omain2

[4546

121]

Lossof

functio

nTo

xicg

ainof

functio

n[107]

Abno

rmalsurfa

ctant

processin

gtraffi

cking[45122]

Lossof

epith

elialfunctio

n[41]

Increase

ofER

stress[4144]

TERT

AEC

type

II[123]

Lung

fibroblasts

[124125]

Lung

epith

elialcells

[126]

Enzymeintelomerase

complex

maintaining


All[555660131ndash135]

Haploinsufficiency

[56136137]

Telomeres

hortening

[55566162124131138139]

TERC

AEC

type

II[70123140]

Lung

fibroblasts

[124125]


complex

[127ndash130]

Pseudo

knotC

R4-C

R5and

ScaR

NAdo

mains

[555661133139141142]

Haploinsufficiency

[136137143144

]Telomeres

hortening

[555661124131138]

DKC

1Lu

ngtissue[145]

Dyskerin

(stabilizes


complex)[64

]

NearR

NA-

bind

ingdo

main

[64]nearN

-term

inus

[146ndash

149]

X-lin

kedlossof

functio

n[64]

Telomeres

hortening[64]

DecreaseinTE

RC[14

6]

TINF2

Lung

tissue[150]

Telomerem

aintenance

byshelterin

complex

[151]

Exon

6resid

ues2

69ndash298

[63152153]

Dom

inantn

egative[63]

Telomeres

hortening[63]

RTEL

1Not

detectablein

lung

s[154155]

DNAhelicasetelomere

T-loopand

G4un

winding

[156]

Vario

usdo

mainsthatis

helicasea

ndharm

onin

[65ndash67157]

Haploinsufficiency

[66]

Telomeres


PARN

Lung

tissue[158]

Exoribon

ucleasec

ontro

lsmRN

Astability[159]

MainlyCA

F1rib

onuclease

domain[67]

Haploinsufficiency

[67]

Telomeres

hortening[67]

Redu

ctionof

DKC

1TE

RT

TERC

and

TERF

1[159]

lowast

Genefun

ctionsuggestedto

beinvolved

inIIPpathogenesis




















IL1RN






TERT



rs2736100 major Aallele [86 97 98 164]




Expression uarr[83]



allele [86 98]



IVD

























Airway epithelium

AEC type I

Capillary


AEC type II

Alveolar surfactant

Claraclub cell

Submucosal gland

MUC5Bproduction


Fibrogenesis









References














































3mutants associ-














































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table1Mutated

genesinIIPexpressin

gpu

lmon

arycellsfun

ction

andmutationalcon

sequ

ences

Gene

Expressin

gcells

inlung

Genefun

ctionlowast

Mutated

domain

Effecto

fmutation

Pathologicalprocess

SFTP

CAEC

type

II[107]

Com

ponent

ofsurfa

ctant

fluid

Lower

surfa

cetension[107]

Link

erdo

mainassociates

with

LB[31]

Toxicg

ainof

functio

n[107]

Alteratio

nof

traffi

cking

dysregulationof

proteosta

sis[31]

Alteratio

nof

surfa

ctantlipid

compo

sition[31]

C-term

inalBR

ICHOS

domainfolded

inER

and

GA[108]

ERstr

essa

ndUPR

upregu

latio

n[109ndash111]

Activ

ationof

immun

ecells[112]

Alteratio

nof

surfa

ctantlipid

compo

sition[112]

SFTP

A2

AEC

type

IIClaraclu

bcell

Subm

ucosalgland

[113ndash116]

Collectin

(tomod

ulate

innateandadaptiv

eim

mun

ity)[107117

]

Carboh

ydrate-recognitio

ndo

main[32]

Toxicg

ainof

functio

n[118]

Increase

ofER

stress[118

]UPR

upregu

latio

n[35119

]

ABCA

3AEC

type

II[120]

Limiting

mem

branep

rotein

oflamellarb

ody[107]

Intracellularloo

pextracellulard

omain2

[4546

121]

Lossof

functio

nTo

xicg

ainof

functio

n[107]

Abno

rmalsurfa

ctant

processin

gtraffi

cking[45122]

Lossof

epith

elialfunctio

n[41]

Increase

ofER

stress[4144]

TERT

AEC

type

II[123]

Lung

fibroblasts

[124125]

Lung

epith

elialcells

[126]

Enzymeintelomerase

complex

maintaining


All[555660131ndash135]

Haploinsufficiency

[56136137]

Telomeres

hortening

[55566162124131138139]

TERC

AEC

type

II[70123140]

Lung

fibroblasts

[124125]


complex

[127ndash130]

Pseudo

knotC

R4-C

R5and

ScaR

NAdo

mains

[555661133139141142]

Haploinsufficiency

[136137143144

]Telomeres

hortening

[555661124131138]

DKC

1Lu

ngtissue[145]

Dyskerin

(stabilizes


complex)[64

]

NearR

NA-

bind

ingdo

main

[64]nearN

-term

inus

[146ndash

149]

X-lin

kedlossof

functio

n[64]

Telomeres

hortening[64]

DecreaseinTE

RC[14

6]

TINF2

Lung

tissue[150]

Telomerem

aintenance

byshelterin

complex

[151]

Exon

6resid

ues2

69ndash298

[63152153]

Dom

inantn

egative[63]

Telomeres

hortening[63]

RTEL

1Not

detectablein

lung

s[154155]

DNAhelicasetelomere

T-loopand

G4un

winding

[156]

Vario

usdo

mainsthatis

helicasea

ndharm

onin

[65ndash67157]

Haploinsufficiency

[66]

Telomeres


PARN

Lung

tissue[158]

Exoribon

ucleasec

ontro

lsmRN

Astability[159]

MainlyCA

F1rib

onuclease

domain[67]

Haploinsufficiency

[67]

Telomeres

hortening[67]

Redu

ctionof

DKC

1TE

RT

TERC

and

TERF

1[159]

lowast

Genefun

ctionsuggestedto

beinvolved

inIIPpathogenesis




















IL1RN






TERT



rs2736100 major Aallele [86 97 98 164]




Expression uarr[83]



allele [86 98]



IVD

























Airway epithelium

AEC type I

Capillary


AEC type II

Alveolar surfactant

Claraclub cell

Submucosal gland

MUC5Bproduction


Fibrogenesis









References














































3mutants associ-














































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































IL1RN






TERT



rs2736100 major Aallele [86 97 98 164]




Expression uarr[83]



allele [86 98]



IVD

























Airway epithelium

AEC type I

Capillary


AEC type II

Alveolar surfactant

Claraclub cell

Submucosal gland

MUC5Bproduction


Fibrogenesis









References














































3mutants associ-














































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















IL1RN






TERT



rs2736100 major Aallele [86 97 98 164]




Expression uarr[83]



allele [86 98]



IVD

























Airway epithelium

AEC type I

Capillary


AEC type II

Alveolar surfactant

Claraclub cell

Submucosal gland

MUC5Bproduction


Fibrogenesis









References














































3mutants associ-














































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























Airway epithelium

AEC type I

Capillary


AEC type II

Alveolar surfactant

Claraclub cell

Submucosal gland

MUC5Bproduction


Fibrogenesis









References














































3mutants associ-














































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Airway epithelium

AEC type I

Capillary


AEC type II

Alveolar surfactant

Claraclub cell

Submucosal gland

MUC5Bproduction


Fibrogenesis









References














































3mutants associ-














































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















































3mutants associ-














































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















3mutants associ-














































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Understanding Idiopathic Interstitial ...downloads.hindawi.com/journals/bmri/2015/304186.pdf · [, ]. ese numbers may even be an underestimation, because the studies