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Chronic inflammation and lung fibrosis: pleotropic syndromes but limited distinct phenotypes A H Gifford1,6, M Matsuoka1,6, L Y Ghoda2,3, R J Homer4 and R I Enelow1,5 1Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA 2Department of Neurology, Beckman Research Institute, City of Hope Medical Research Center, Duarte, California, USA 3Keren Pharmaceuticals, San Mateo, California, USA 4Department of Pathology and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, and VA Connecticut Healthcare System, West Haven, Connecticut, USA 5Department of Microbiology/Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA Correspondence: RI Enelow, (Richard.firstname.lastname@example.org) 6The first two authors contributed equally to this work. Received 4 April 2012; Accepted 13 June 2012 Advance online publication 18 July 2012 Mucosal Immunology (2012) 5, 480–484; doi:10.1038/mi.2012.68; published online 18 July 2012 Abstract Experimental models of lung fibrosis have been disappointing in predicting therapeutic responses to a wide variety of interventions in clinical fibrosing lung diseases. There are multiple potential reasons, but this fundamentally calls into question the validity of the models and their fidelity to clinical syndromes. We propose that the clinical diseases associated with pulmonary fibrosis, although manifesting a broad array of widely different clinical presentations and features, result in essentially two distinct phenotypes of fibrosis that we will describe. The most common and problematic of these are not effectively modeled experimentally. In this review, we present several clinical entities as examples of the phenotypic distinctions. The first two represent the extremes: postinflammatory fibrosis observed in hypersensitivity pneumonitis (HP) and dysregulated matrix deposition as observed in idiopathic pulmonary fibrosis (IPF). We also present a third clinical entity, that of lung disease associated with rheumatoid arthritis (rheumatoid lung), representing a condition that can manifest as either phenotype, and offering a potential opportunity to explore the mechanisms underlying the pathogenesis of the two distinct fibrotic phenotypes.