The pathogenesis of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a restrictive pulmonary disorder of unknown aetiology with a relentless disease course and a median survival of 3 years after the diagnosis. It is the most common idiopathic interstitial lung disease (ILD) with a basal and peripheral predominance associated with temporal and geographical heterogeneity. As the pathogenesis of this disease is poorly understood, the aim of this work was to investigate the pathobiology of IPF in a prospective manner. There is evidence of a strong association of gastro-esophageal reflux and vascular disease with IPF. Moreover, a proportion of patients have evidence of immunological antibodies without any evidence of connective tissue or autoimmune disease. The data presented in this thesis suggest that platelet-monocyte complexes may be involved in the pathogenesis of IPF at molecular level as suggested by the flow cytometric data utilizing monoclonal antibodies to platelets (CD42a) and monocytes (CD14). Moreover, expression of CD40L, P-selectin and PSGL-1 on platelets and subpopulation of leukocytes suggested that platelet expression of these molecules is not significantly different in IPF as compared to ILD other than IPF or non-ILD controls. Furthermore, platelet mediated injury hypothesis is supported by significant elevation of platelet endothelial cell adhesion molecule in plasma of IPF patients. Reflux of gastric secretions into the tracheo-bronchial tree is another attractive hypothesis in light of remarkably high prevalence of gastro-esophageal reflux disease (GERD) in IPF. The data suggest that patients with IPF have significantly higher gastro and extra-esophageal reflux symptoms when assessed by Hull airway reflux questionnaire (HARQ). However, there was a lack of objective evidence of extra-esophageal reflux measured by exhaled breath pepsin concentration or significantly higher prevalence of Helicobacter Pylori. Furthermore, there was evidence of immune mediated injury in IPF by indirect immunofluorescence study of alveolar epithelial (A549) cells as significant membranous enhancement of A549 cells by anti-IgG antibodies was demonstrated in IPF patients’ sera. However, Human umbilical vein endothelial cells (HUVEC) did not show any differential staining pattern with either anti-IgG or IgM. Hence, there is a suggestion of alveolar epithelial disruption mediated by immune mechanisms with a predominant involvement of IgG antibodies. Furthermore, epithelial derangement may extend into the respiratory epithelium with release of carcinoembryonic antigen (CEA) in peripheral circulation as evidenced by a significant correlation of raised CEA level and lung function impairment in IPF. These findings provide clinical and molecular evidence of novel mechanisms of pathogenesis of IPF with increased platelet-monocyte aggregation. Moreover, immune mediated alveolar epithelial dysfunction involving IgG antibodies may provide further insight into the understanding of the pathogenesis and natural history of this fibrotic disease