The pathogenesis of pulmonary fibrosis: Is there a fibrosis gene?

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Abstract

Interstitial fibrosis is seen in the lung in response to a variety of insults, and often appears stereotypical in terms of its clinical and pathological features. However, exposure to a known aetiological factor does not always lead to fibrosis. For example in bleomycin-induced pulmonary fibrosis, a wide variation in response is seen both in humans and in animal models, which is not completely accounted for by known risk factors. These observations and the existence of a number of familial forms of lung fibrosis suggest a genetic predisposition. Current hypotheses concerning the pathogenesis of pulmonary fibrosis propose an initial stage involving the influx of inflammatory cells into the interstitium. These cells, together with activated resident cells are then thought to release polypeptide mediators that stimulate the fibroblast proliferation and matrix protein synthesis typical of these disorders. Genetic influences could have an important role in regulating a number of these events, altering the immunological response to injury or modulating collagen metabolism in the lung. However, despite recent advances in molecular genetic techniques, there have been few human studies to date. Most have concentrated on genetic loci with a high degree of polymorphism such as the human leucocyte antigen (HLA) system and yield conflicting results. Others offer tantalising but as yet, incomplete insights into the mechanisms involved. Defining the genetic abnormalities underlying both the familial forms of pulmonary fibrosis and the variations seen in response to lung injury should enhance our understanding of the pathogenic processes and help to focus research in this area.

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