RESEARCH & DEVELOPMENT

Filling the gaps in therapy for pulmonary fibrosis

-Rodger Hall-

Researchers are turning to growth factors and glutathione in attempts to find new approaches for the preventionand treatment of pulmonary fibrosis. In particular, pretreatment with fibroblast growth factor-7 prevents bleomycin­induced pulmonary injury in animals, and strategies that increase alveolar cell glutathione concentrations may beeffective in limiting pulmonary fibrosis. These approaches to therapy, as well as suggestions for improving clinicalstudies in patients with pulmonary fibrosis, were discussed at the Annual International Meeting of the AmericanLung Association and the American Thoracic Society [Seattle, US; May 1995].

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Dr Bob Mason from Denver, US, described severalgrowth factors that are present in pulmonary fibrosis:• transforming growth factor-a (an autocrine growth

factor that stimulates the growth of type II alveolarcells)

• acidic fibroblast growth factor• heparin-binding epidermal growth factor• hepatocyte growth factor• fibroblast growth factor-7 (FGF-7; keratinocyte

growth factor).

FGF-7 prevents pulmonary injuryDr Mason's group has concentrated on

investigating the effects of FGF-7.FGF-7 plays an important role in fetal lung develop­

ment, and also stimulates the growth of type II alveolarcells. Type II alveolar cell proliferation is an import­ant part of the response to lung injury. FGF-7 is alsoinvolved in the maintenance of normal alveolar archi­tecture and pulmonary gas exchange. These processesare thought to promote lung repair and minimise sub­sequent fibrosis.

In in vivo studies in animals, pretreatment withFGF-7 prevented bleomycin- and hyperoxia-inducedpulmonary injury. 'This growth factor warrantsfurther study as a potential new therapy', said DrMason.

Manipulating puhnonary fibroblast growth'In pulmonary fibrosis, the fibroblasts are on

a mission to fill in the air space' , said Dr P Bittermanfrom Minneapolis, US. When isolated, the fibroblastshave the appearance of transformed cells rather thannormal resting fibroblasts, and they will proliferatein the absence of growth factors, according to DrBitterman.

This suggests 2 possible strategies for antifibrotictherapy. Growth factor-dependent antifibrotic strate­gies could be targeted at preventing ligand release,modulating ligand-receptor interactions, and inter­fering with signal transduction. Growth factor­independent approaches could be directed at haltingfibroblast cell-cycle progression by inducing the p53gene, identifying naturally occurring inducers of fibro­blast apoptosis, and altering the susceptibility of fibro­blasts to apoptosis.

Glutathione has potential for treatingpuhnonary fibrosis

Dr AM Cantin, Centre Hospitalier Universitairede Sherbrooke, Quebec, Canada, discussed the roleof glutathione in alveolar epithelial cell proliferation.

Glutathione synthesis precedes alveolar cell pro­liferation, and its presence is essential for the cells

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to respond to mitogens and initiate cell division. Incre­ases in alveolar glutathione levels enhance alveolarcell proliferation in response to mitogens. In addition,glutathione prevents the cytokine-induced activationof the transcription factor nuclear factor-xls (NF-KB).This suggests that low alveolar glutathione levels mayfavour the expression of certain inflammatory cyto­kines.

Dr Cantin commented on several strategies thathave been investigated in attempts to increase alveolarcell glutathione content [see table].

Potential strategies for increasing alveolar cellglutathione concentrations

Strategy Comment

Administration of aerosolised Transient increase in glutathione,glutathione but rapid oxidation occursAdministration of acelytcysteine High doses of up to 1.8 glday(glutathione precursor) reqUired; unpleasant taste

Antioxidant vitamin therapy Not yet investigated

Glutathione administered as Increases cell ular glutathioneHpid-soluble diester in animals

Glutathione-containing liposome Increases cellular glutathioneadministration in vitro

Inhibition of TGFIl expression or Possiblewith monoclonalactivation antibodies ordecorin?

Inhibiting the expression or activation of trans­forming growth factor-B (TGFP), by using mono­clonal antibodies or decorin (a naturally occurringinhibitor of TGFP), may represent one of the mostlogical approaches to increasing alveolar glutathioneconcentrations. TGFp decreases glutathione contentin alveolar epithelial cell lines by downregulating thegene that codes for garnma-glutamyl cysteinesynthetase, the rate-limiting step in glutathionesynthesis. TGFp expression appears to be one of thefactors involved in hyperoxia-induced fibrosis.

1Iials must testnew therapeutic strategiesAccording to Dr G Raghu from the University

of Washington, Seattle, US, 'current treatments [foridiopathic pulmonary fibrosis] are not very effectiveand there has been no significant progress in deve­loping clinical trials to test new therapeutic strategiesand treatments'. However, Dr Raghu listed severalcurrently available drugs, and some new approaches,that could be investigated in future studies in pulmo­nary fibrosis [see boxed text over page].

A regimen comprising low-dose prednisonein combination with azathioprine has been studiedin a prospective, double-blind, randomised trial inpatients with pulmonary fibrosis.' All patients (n =27)received oral prednisone 1.5 mg/kg/day (maximumdaily dose 100 mg/day) tapered to a maintenance dose

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10 RESEARCH & DEVELOPMENT

Pulmonary fibrosis - continued

of 20 mg/day. They were additionally randomisedto receive either azathioprine 3 mg/kg/day (maximum200 mg/day), or placebo.

6/14 patients who received prednisone incombination with azathioprine died during the 9-yearfollow up period, compared with 10/13 patientstreated with prednisone alone. The survival advantagewith the combination regimen was marginallysignificant when adjusted for age. Although theevidence from the study was not sufficient to makeclinical recommendations, the investigators concludedthat a larger randomised study was warranted toconfirm their results.

Plea for international co-operationDr R M du Bois from the Royal Brompton

Hospital, London, UK, made a plea for internationalco-opera-tion in the fight again st pulmonary fibrosis. He saidthat 'despite the explosion ofmolecular technologyover the last decade, progress has been sideways,with advances in the understanding of mechanismsnot being matched by application to clinical man­agement'. He emphasised that minimum standardsof care need to be established, and studies are requiredto evaluate current protocols. 'It is only by estab­lishing protocols with clear outcome measures thatmore innovative approaches can be tested, and thestructure for these should be put in place now', Drdu Bois said.

A delegate attending the session supported the needfor new approaches, saying that a 'Z-pronged' attackwas required. First, clinicians need help in identifyingtarget molecules and in setting up appropriate trials .

1 Jul 1995INPHARMA"

Candidates for future clinical trialsinpulmonary fibrosis

• Low-dose corticosteroids in combination withanother immunosuppressive agent

• Colchicine• Methotrexate• Cyclosporin• Interferon-y• Interleukin-1 receptor antagonists• Surfactants• Antioxidants• Cell adhesion molecule antagonists• Anticytokines, cytokine receptor antagonists• Antifibrotic agents e.g. pirfenidone [DeskarThl

;

phase II)

Second, better outcome measures are urgently required,and are crucial for the effective evaluation of thera­peutic interventions. 'In particular, surrogate markersand intermediate indices are needed. Survival timeis not a good enough measure for testing newapproaches to treatment in a chronic disease',he said.

Dr Gordon Snider from the Boston UniversitySchool of Medicine, US, believes that a marker reflec­ting the progression of pulmonary fibrosis is needed.He suggested that researchers should start searchingfor a molecule that is expressed in serum, and thatchanges in concentration with disease progression.

I. Raghu G. et al, Azathioprine co mbined with prednisone in the treatment of

idiopathic pulmonary fibrosi s: a prospective double-blind. randomized.placebo-controlled clinical trial. American Review of Respiratory Disease 144:

291·296. Aug 1991 >1003144%

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