Understanding the Biology of Pulmonary Fibrosis: What Genes Tell Us for Idiopathic Interstitial Pneumonia

Pulmonary fibrosis is the formation of fibrous tissue as a reaction or a repair process in the lung. It is the main cause of severe morbidity and mortality in interstitial lung disease (ILD). Pathogenesis in most ILDsis triggered by exposition to exogenous factors, such as asbestos and radiation, or endogenous factors, such as auto-immune disease and drugs. However, in a subgroup of ILD, the idiopathic interstitial pneumonias (IIPs), causative environmental triggers have not been identified. Fibrogenesis in IIP seems to be an autonomous pulmonary process, making a strong genetic contribution to disease more plausible. In fact, in the last decade, several studies have shown a contribution of genetic variations to the development of IIP, from highly penetrant mutations to strongly predisposing common risk alleles. This review summarises the results of candidate gene analyses, family-based linkage analyses, and case control whole genome association studies that have identified germ-line gene variants that predispose to the development of IIP. Genetic analyses in both familial and sporadic diseases have shown congruent results and point to genes, their corresponding protein product, and effect on cell function in several pathways. Present data tell us that IIP result from a complex interaction involving the alveolar compartment, in particular alveolar epithelial Type 2 cells, but recent studies also emphasise a role for mucin and immune-regulatory genes.