Mechanisms of Lung Fibrosis Resolution

Abstract

Fibrogenesis involves a dynamic interplay between factors that promote the biosynthesis and deposition of extracellular matrix along with pathways that degrade the extracellular matrix and eliminate the primary effector cells. Opposing the often held perception that fibrotic tissue is permanent, animal studies and clinical data now demonstrate the highly plastic nature of organ fibrosis that can, under certain circumstances, regress. This review describes the current understanding of the mechanisms whereby the lung is known to resolve fibrosis focusing on degradation of the extracellular matrix, removal of myofibroblasts, and the role of inflammatory cells. Although there are significant gaps in understanding lung fibrosis resolution, accelerated improvements in biotechnology and bioinformatics are expected to improve the understanding of these mechanisms and have high potential to lead to novel and effective restorative therapies in the treatment not only of pulmonary fibrosis, but also of a wide-ranging spectrum of chronic disorders.

Figure 1

Conditional TGFα transgenic mice induce transgene expression following enteral administration of doxycycline (Dox). Pentachrome stains of subpleural regions in TGFα mice without Dox (A) after 42 days of Dox (B) and 42 days on Dox followed by 126 days off Dox (C). Right ventricular (RV) hypertrophy measured by comparing RV divided by left ventricle plus septal weight (RV/LV + S) at intervals on and off Dox (D). Reprinted from Hardie et al with permission of the American Thoracic Society. ^∗P < 0.05 versus control.

Figure 2

Collagen internalization is mediated by macropinocytic, phagocytic, and endocytic pathways where fragments are ultimately degraded by the lysosome. Figure modified from McKleroy et al with permission from the American Physiological Society. Mfge8, milk fat globule–epidermal growth factor 8; uPARAP, urokinase plasminogen activator receptor–associated protein.