1992 - The Senile Lung

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    As part of a study of the structural-functional correlations

    o fe xc is ed h um a n lu ng s o bta in ed a t a uto ps y, t he p ar en ch ym a

    and peripheral airw ays w ere exam ined by m eans of m or.

    p ho me tric te ch niq ue s. A m on g th e 3 0 lu ng s c ha ra cte riz ed

    b y th e a bse nc e o ffib ro sis , te n d iffe re d fro m th e n orm al a nd

    em ph ysem ato us lu ng s b y a h om oge neo us d ilatatio n o f th e

    airspaces, in excess of the dim ensions predicted on the

    b asis o f ag e. S tu dy o f th e stan dard d eviatio ns o f th e m ea n

    linear intercepts showed that the airspace dilatation was

    m ore reg ular th an in em ph yse mato us lu ng s; in ad ditio n,

    th ere w as n o cle ar-cu t destru ctio n, as estim ated from th e

    number of alveolar attachm ents. These lungs were char

    a cte ri ze d in a dd iti on b y a n in cr ea se d th ic ke nin g o f a lv eo la r

    se pta , w ith ou t in fla mm atio n o r fib ro sis, n orm al s iz e o f th e

    diam eter, and reduced density of the m em branous bron

    ch io les. S in ce th ese lun gs w ere from p eo ple o ld er th an 6 0

    y ea rs , it is a ss um e d th at th ey re pr es en t c as es o f e xa gg er ate d

    airspace enlargement of the aging lung, differing from

    e mp hy se ma b y th e a bs en ce o f d estru ctio n o f a lv eo la r w alls .

    T he term senileungs p ropos ed f or t hi s cond it ion .

    C h e s t 1 9 92 ; 1 0 1: 79 3 -9 9 )

    AA = alveolar attachm ents; CLE centrilobular emphysema;

    CV= coefficient of variation; J mean diameter; Lm m ean

    linear intercept; Lm a Lm air; Lm w Lm wall m ean transec

    tion length per airspace; n/sq cm density; N1 num ber of

    intercepts; SDN ,standard deviation of N I

    A recent report of the N ational H eart, Lung, and

    Blood Institute' defines em physem a as a condi

    tion ofthe lung characterized by abnorm al, perm anent

    enlargem ent of airspaces, accom panied by the de

    struction of their walls and without obvious fibrosis.

    Destruction m ay be recognized by the disorder of the

    respiratory a irsp aces. Singleirspace enlargement,

    on the other hand, is described as an increase in

    airspace size, distal to the term inal bronchioles, as

    com pared w ith the airspaces of norm al lungs. There is

    no evidence of destruction. The process m ay be

    acquired, as in the uniform respiratory airspace en

    largem ent of the aging lung.

    In a study of the functional-m orphologic correlates

    of em physem a, we exam ined a num ber of lungs

    obtained at autopsy. Som e ofthese lungs were norm al;

    others were clearly em physem atous. A third group of

    lungs, however, demonstrated an enlargem ent of air

    spaces, m arkedly larger than that expected on the

    basis of aging alone. O riginally, our hypothesis w as

    that these lungs dem onstrated panacinar em physem a.

    However, the absence of any disorganization by low

    power m agnification and of inflam mation at the level

    of the airspaces and of the peripheral airways at the

    m icroscopic level prom pted us to reconsider our

    * F mm t he L a bo ra to ri um v oo r P n eu m ol og ie e n P at ho lo gi se he O n t

    le ed ku nd e I U niv ersita ire Z ie ke nh uiz en S t. R afa el, G asth uisb erg ,

    L eu ve n, B elg iu m.

    S upported by a grant of the F onds voor G eneeskundig W eten

    schappelijkOnderzoek.

    M anuscript received February 14; revision accepted July 16.

    R eprint requests: Dr. V arbeken,Laboratorium voor HLstopathologie ,

    K a@ n jn en vo er 3 3, B -3 00 0 L , @ uv en ,Belgium

    opinion. W e w ondered if w e w ere not dealing with

    in stan ces o f ex ag gerated resp irato ry airsp ace enlarge

    m ent rather than w ith em physem a. To substantiate

    this im pression, we perform ed a system atic m orpho

    m etric stud y o fairsp aces a nd m em bran ou s b ro nc hiole s

    in an attem pt to distinguish on an objective basis these

    lungs from norm al and truly em physem atous lungs.

    M ATERIAL AND M ETHODS

    Studies were performed on 17 right and 12 left human lungs and

    one isolated left low er lobe (V 50), obtained a t autopsy. L ungs w ere

    selected on the basis of absence of marked pleural adhesions and

    l ea ks , g ro ss p ar en ch ym a l c on so lid at io ns , a nd /o r g en er al iz ed f ib ro sis .

    M ost lungs w ere from patients w ho died of cardiovascular disease

    or of m alignant neoplasm s. T he exa mined lungs represent a sam ple

    that can be considered unselected at least from the population of

    patients for whom an autopsy was being asked @ nour general

    hospital. An exception was made for three lungs (V50, V51, V52)

    th at w ere selected b eca use o f clin ica l sev ere ch ro nic o bstru ctiv e

    l un g d is ea se a nd /o r th e p re su mp ti on o f a dv an ce d e mp hy se ma .

    F ol lo win g t he f un ctio na l m ea su re me nts ( se e c om pa ni on a rti cle ),

    t he l un gs w er e p er fu se d in tr ab ro nc hia lly f or a t l ea st 7 2 h w it h a 1 0

    percent formalin solution, at a pressure of 2.5 to 3.0 kPa. W hole

    lu ng sectio ns w ere p rep ared fro m 2 6 lu ng s fo llo win g th e tech niq ue

    of Gough and W entworth.2 The lung was cut into 1.5-cm-thick

    sagittal slices and a 0.4-m m-thic k w hole lung section w as prepare d

    from the m idsa gittal slice. T he rem aining lung tissue of that section

    w as also exam ined under the dissection m icroscope. The degree of

    airspace enlargement was assessed on the whole lung section by

    means of a plastic Ryder grid.@ This grid divides the lung in ten

    equal radiating segm ents. To each segm ent an emp hysem ascore

    from 0 (no enlargement) to 3 (severe enlargement) is given, the

    m axim al score thus being 30. F inally, tis ie blocks w ere selected

    according to the following protocol. Twelve to 15 random tissue

    blocks w ere chosen from each lobe separately: the blocks w ere cut

    from both upper and lower lobes parallel to and about 1 cm from

    CHEST I 101 I 3 I M ARCH, 1992 793

    TheSeni leLung*

    Comparisonwith Normaland EmphysematousLungs

    1 . Structural A spects

    Erik K . Verbeken, M .D .; M ichel Cauberghs, B.S.; Ingrid M erten@ M .D .;

    Jacques C lem ent, M .D .; Joseph M . L auw eryn@ s@ , .D ., P h.D .; and

    K arel P Van de W oestijne, M . D . , P h.D .

    wnloaded From: http://journal.publications.chestnet.org/ on 10/06/2013

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    ABCDuncan's

    estAge,

    yr49.1

    20.369.94.861.36.5A,BB,CBody

    le ng th , c m 16 6

    1116691667A,

    B,Emphysemascore1.21.69.14.614.35.4ABCLm,

    mm0.2890.0390.4920.0940.5840.140ABCLm%predt105.69.5165.631.6203.047.2ABCNI5.490.723.260.552.84

    CSDN,3.220.282.060.242.420.39ABCSDN/NI

    x 100%59.34.264.07.487.5

    11.0A,

    CLma,

    mm0.2650.0350.4530.0840.5300.123ABCLma%predt100.08.5156.028.8189.142.5ABCLmw,

    mm0.0240.0050.0390.0110.0540.017ABCLmw%[email protected]@l,

    mm0.800.090.850.140.510.09A,

    Cn/sqcm0.850.110.700.150.640.11AB,CAA/mm6.720.876.750.915.760.72A,

    BC

    th e p leu ra l su rfac e. In co mp le te ly e xpa nd ed lu ng reg io ns w ere

    carefully avo ided. P araffin sections, 4 @ tm hick, w ere prepared in a

    standard way, and stained with M asson's trichrome. Since the

    shrinka ge from fixe d lung to histologic slide is fairly constant even

    in different pathologic conditions, a constant shrinkage factor of

    0.61 w as used.' T he stained slices w ere exam ined by light m icros

    c op y w it h a x 1 0 e ye pi ec e a nd a X 1 0 p Ia no -o bj ec ti ve ( m ag ni fi ca ti on

    x 1 00).

    T he m ean linear intercept, L m, w as m easured follow ing the

    te ch niq ue o f D un nil l.' B ri efl y, c ro ss ed h ai r li ne s w ith k no wn l en gth

    a re p ro je ct ed o n th e p ar en ch ym a, a nd t he i nte rs ec ti on s b et we en

    lines and alveolar septa are counted.' The length ofthe line divided

    by the num ber of intercepts (NI) yields Lm. To partition Lm into

    its two com ponents, namely the m ean transection length, which

    reflects the thickness of the septal wall (Lm wall:Lmw) and the

    in te rn al d ia me te r o fth e a ir sp ac es (L m a ir :L ma ), D un nill's te ch niq ue

    w as slightly m odified by adding a point counting m ethod. The hair

    lin e w as d iv id ed in 1 00 eq ua lly d is ta nt p oin ts , w ith a p oin t sp acin g

    o f t he la tt ic e ( Ze is s K pl W 1 0x / 18 ) o f 0 .0 09 55 m m a t a m ag ni fi

    cation of 100 tim es. The sum of the points falling over the

    parenchym a equa ls the tota l transection length of the parenchym a.

    Dividing the latter by NI yields the m ean transection length per

    airspace (Lmw). Two hundred points were counted for each of the

    120 m icroscopic fields investigated per lung, thus ensuring a

    s tatis tica lly re pre sen ta tiv e s am ple .@

    Since Lm is known to be a hm ction of age in norm al lungs,6(b0

    L m is expressed in percent predicted, using the regression of

    Thurlbeck@ : Lm 0.0011 age+0.2174. In agreement with the data

    of Thurlbeck, airspace enlargem ent w as considered to be exag

    g er ate d w he n L m e xc ee de d 1 20 p e rc en t o fit s p re di ct ed v al ue .

    T o e va lu ate o bje ctiv ely th e u nifo rm ity o f a ir sp ac e e nla rg em en t,

    w e d ete rm in ed th e s ta nd ar d d ev ia ti on o f N I. T he l att er ( SD N ,)i s a

    f un ct io n o f ( 1) t he i nh om og en ei ty o f t he a lv eo la r s iz es , a nd ( 2) t he

    a ve ra ge a lv eo la r s iz e, th e la rg er t he a lv eo li , th e le ss th e n um b er o f

    intersects (pro vided the optical m agn ification re mains constant),

    and thus the sm aller S DN ,. A ccordingly , to estim ate the uniform ity

    of airspace enlargem ent, w e used the coefficient of variation of N I:

    S D N,d iv id ed b y t he m ea n v al ue o f N I. W it h t he e xc ep ti on o f t hr ee

    l un gs . b ot h N I a nd S D N Iw e re a ls o d et er m in ed s ep ar at el y f or u pp er

    a nd lo we r lo be s.

    As an index for destruction, we counted the number of alveolar

    a tta ch me nts o n m em bra no us b ro nc hio le s (th e n on alv eo la te d p erip h

    eral airways w ithout cartilage or m ucous glands in their w alls) per

    m il li me te r o fp er im e te r ( AA /m m ). 1 2 F or e ac h lu ng w e m e as ur ed

    the internal diam eter and the corresponding A A from seven

    m em branous bronchioles both in the upper and low er lobes. These

    1 4 a ir wa ys , c ho se n a t r an do m, h ad to m ee t t he f oll ow in g c ri te ria :

    their walls had not been sectioned because they were adjacent to

    t he e dg e o ft he b lo ck , t he p or ti on b or de re d b y a cc om p an yi ng b lo od

    vessels did not exceed 25 percent of the total perimeter, and the

    s ec ti on w a s ( al m os t) c om p le te ly t ra ns ve rs al .

    T h e i nt er na l d ia m et er o fa t l ea st 2 3 m e m br an ou s b ro nc hi ol es p er

    lobe, with an internal diam eter of 2 m m or less, was m easured

    f ol lo w in g t he t ec hn iq ue o fM a ts ub a a nd T h ur lb ec k. A ir wa y d en si ty

    (n /s q cm ) w as def ined as t he num ber o f m em branous b ronch io le

    a irw ays per square centim eter oflung tissue; n/sq cm w as m easured

    b y a L eitz im age a nalysis system .

    RESULTS

    The lungs w ere divided into three groups on the

    basis of the global aspect of the parenchym a on the

    whole lung sections (exam ined by eye and under the

    dissection m icroscope) and of the value of Lm . Lungs

    of group A had a norm al aspect, the value of Lm did

    not exceed 120 percent of expected. In the lungs of

    groups B and C, the value of Lm w as higher than 120

    percent. T he enlargem ent ofthe respiratory airspaces

    w as hom ogeneous in group B, irregular in C. M or

    phologically the lungs of group C were typical for

    centrilobular em physem a (CLE). A ccording to the

    clin ical histo ry , g ro up A co nsisted o f five n on sm ok ers,

    four current sm okers, and one exsm oker. N one had a

    history of chronic bronchitis. In group B, three sub

    jects were sm okers, two w ere exsm okers, and one w as

    a nonsm oker. The sm oking habits were not docu

    m ented in three subjects. Two subjects had a history

    ofchronic productive cough. Group C consisted of six

    current sm okers, three exsm okers, one nonsm oker,

    and one unknown. Eight subjects of group C had a

    T ab le 1 B io me trica nd M o rp lso me tric D ata O ftlse T hre e G ro up s o flrn sg a: A N orm al,' B S en ile ;

    C= Emphyseina tous b ings Mean ValuesStandard Deviat ion 5

    *Duncan's multiple range test: the dashes indicate a significant (p

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    history ofchronic productive cough. The m ean values

    (1 SD) of the biometr icand morphom etr icdataof

    the three groups of lungs are listed in T able 1.

    R es pira to ry A ir s p ac es

    Liii: In agreem ent with Thurlbeck,6 Lm was found

    to depend on age: a sim ilar age dependence was oh

    served in the group of ten norm al lungs (Lm =

    0.0014 age + 0.2202, p

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    a dd itio na l tio rin al lu ng s w e@ -c nc lu de d iii tlu ' n uh lti1 )lc

    regression . ) Both Li@ a and Lin@ v a re sign ifican tl@

    d ifferen t @ tfl1O I1 ghe threc g,oii@ )s of slil)jccts, @ tIS()

    @@he nh e@ ' a rc ( o rrec te(l fo r ag e (L n@ a), u r fo r ag e,

    height, and lung @ @ eightL iii@ @ )(T ab le 1 ). A tig ht

    correlation @ @ sound l)et\v('('ll Lii@ a and L,ii@ @ f or the

    three gronp@ of lungs coiisidered together (r: 0.95,

    1)

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    relationship is found in em physematous lungs between

    d and Lm a (r: 0.68; p

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    lungs. T he latter increase in thickness, also described

    by Anderson et al,'@ '@in em physem atous lungs is not

    easily observed by eye: it is only in advanced em phy

    sem a th at a d iffu se th ick en in g o fth e w alls su rro un ding

    large holes is noticed. S im ple histologic exam ination

    does not reveal any differences betw een the increase

    in Lm w in groups B and C.

    T he d en sity ofm em bran ou s b ro nchioles is g en era lly

    reduced in em physem atous lungs2@ ': this is in

    agreement with our findings in CLE. A similar reduc

    tion in density is observed in the lungs ofgroup B. On

    the other hand, bronchiolar diam eter is norm al in

    group B and decreased in em physem a. The latter

    decrease accom panied by an excess of airways with a

    diam eter of 0.6 mm or less has been docum ented

    p re vio us ly b y o th er s.'3 '2 ' @@@@r on ch io la r d ia m et er

    and density are negatively correlated in both groups

    A and B. This relationship, observed by M atsuba and

    Thurlbeck'4 in nonem physem atous lungs and by N agai

    et aP@ in patients with airflow obstruction is not

    observed in em physem atous lungs (Fig 4). In the

    latter, we found in agreem ent with M itchell et aP'nd

    H ale et aF n eg ativ e c orrelatio n b etw een b ro nch io lar

    diam eter and the severity of em physem a, expressed

    by the size of Lm .

    The reduction of bronchiolar diam eter is m ore

    pronounced in the lower than in the upper lobes in

    CLE . In contrast, Lm is larger in the upper lobes.

    This is in agreem ent with the data of Berend,37 who

    observed m ore bronchiolar inflam fnation and narrow

    ing in the lower lobes in CLE and suggested that

    different m echanism s m ay he responsible for sm all

    airways narrow ing and alveolar enlargem ent and/or

    destruction. On the other hand, w e observed an

    inverse relationship in CL E betw een L m and diam eter

    in both upper and lower lobes, considered separately.

    This, in turn, supports the classic idea of a direct

    c ausal relatio nsh ip b etw een sm all airw ay ab no rm ality

    and the occurrence of em physem a.@ '

    In a study of 80 lungs from nonsm okers, A nderson

    et al@ observed the presence of m ild to m oderate

    em physem a of the panacinar type in 20 elderly sub

    jects (60 years or older). T here w as a diffuse dilatation

    of alveolar spaces, distributed m ore or less evenly

    throughout secondary lobules and lobes or lung. A l

    veolar walls were often thickened by subtle, diffuse

    interstitial inflam mation. There w as rupture of alveolar

    structures w ith occasional sim ple dilatation. W e sub

    m it that a num ber of these lungs m ight be categorized

    as senile lungs. The distinction between m ild panaci

    nar em physem a and senile lungs is often very difficult

    by v isu al insp ectio n.3 7 It is im portant th at qu an tita

    tive techniques are developed further for separation

    o fb or de rl in e c as es ( eq ui vo ca l m ph ysem ato us areas

    ofThurlbeck@ ). W e suggest that the determ ination of

    the CV of the num ber of intercepts, counted to

    determ ine L m, is useful for this purpose: a value of

    70 percent appears to separate quite well emphysem

    atous from norm al and senile lungs.

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