The Role of Immunity and Inflammation in IPF Pathogenesis

Butler, Marcus W.; Keane, Michael P.

IPF is thought to be a consequence of repetitive micro-injury to ageing alveolar epithelium by factors including tobacco smoke, environmental exposures, microbial colonisation/infection, microaspiration, endoplasmic reticulum stress and oxidative stress, with resultant aberrant wound healing. Though partially effective antifibrotic therapies have focused attention away from older inflammation-based hypotheses for IPF pathogenesis, innate and adaptive immune cells and processes may play roles potentially in initiation and/or disease progression in IPF and/or in IPF acute exacerbations, based on multiple lines of evidence. Members of the Toll-like family of innate immune receptors have been implicated in IPF pathogenesis, including a potential modulatory role for the lung microbiome. A variety of chemokines are associated with the presence of IPF, and an imbalance of angiogenic chemokines has been linked to vascular remodelling in the disease. Subsets of circulating monocytes, including fibrocytes and segregated-nucleus-containing atypical monocytes (SatM), have been identified that may facilitate progression of fibrosis, and apoptosis-resistant pulmonary macrophages have been shown to demonstrate pro-fibrotic potential. Inflammatory cells that have been somewhat dismissed as irrelevant to IPF pathogenesis are being re-evaluated in light of new mechanistic data, such as activated neutrophils which release their chromatin in a process termed NETosis, which appears to mediate age-related murine lung fibrosis. A greater understanding is needed of the role of lymphoid aggregates, a histologic feature of IPF lungs found in close proximity to fibroblastic foci and highly suggestive of the presence of chronic immune responses in IPF, as are well-characterised activated circulating T lymphocytes and distinct autoantibodies that have been observed in IPF. There is a pressing need to discern whether or not the indisputably present immune dysregulation of IPF constitutes cause or effect in the ongoing search for more effective therapeutic strategies.