FAMILIAL PULMONARY FIBROSIS

家族性肺纤维化（FPF）是一种遗传性肺纤维化疾病

Familial pulmonary fibrosis (FPF) is an inherited fibrotic lung disorder of unknown etiology which is clinically and pathologically identical to idiopathic pulmonary fibrosis except that it occurs in families. The mode of inheritance is compatible with that of an autosomal dominant gene with variable penetrance. The overall goal of this proposal is to study the molecular genetics of familial pulmonary fibrosis. The specific aims are to (1) recruit and clinically characterize families with pulmonary fibrosis and (2) perform restriction fragment length polymorphism (RFLP) analysis on members of these families followed by linkage analysis to candidate genes. It is possible that FPF is due to an abnormality in the gene or group of genes which control immunologic or inflammatory processes. Alternatively, a genetic abnormality in the genes coding for the interstitial collagens may be involved. We propose that genes coding for types I and III procollagen or an HLA locus are candidate genes for the FPF locus. This hypothesis will be tested by performing RFLP analysis on individuals with FPF followed by linkage analysis for these candidate genes. Preliminary data in three families show polymorphism for two restriction enzyme sites for type I procollagen. More families will be recruited and evaluated clinically for the presence of interstitial lung disease. All members of informative families will be studied by analysis of bronchoalveolar lavage (BAL) fluid to detect asymptomatic patients with alveolitis who may be in a preclinical phase of the disease or who may represent incomplete penetrance of the FPF gene. BAL fluid will be evaluated for inflammatory changes and "activated" pulmonary alveolar macrophages. RFLP analysis will be performed by digestion of DNA with restriction endonucleases and Southern blot analysis of the digested DNA fragments using radiolabelled probes for the pro-alpha 2(I), pro-alpha 1(I) or pro-alpha 1(III) chains of collagen as well as a probe for an HLA marker. Linkage analysis will be performed to determine whether FPF is associated with an abnormality in genes coding for types I and III procollagens and an HLA locus. If linkage is shown between the clinical syndrome and a specific genotype, this would provide strong evidence that the disease is due to an abnormality in the collagen genes or the immune system. If established, this finding would have important implications for the pathogenesis of fibrosing lung disorders. It might also have importance in establishing genetic susceptibility to environmental fibrosing lung diseases.