Mechanisms of Pulmonary Fibrosis

Abstract

Tissue injury evokes highly conserved, tightly regulated inflammatory responses and less well-understood host repair responses. Both inflammation and repair involve the recruitment, activation, apoptosis, and eventual clearance of key effector cells. In this review, we propose the concept of pulmonary fibrosis as a dysregulated repair process that is perpetually "turned on" even though classical inflammatory pathways may be dampened or "switched off." Significant regional heterogeneity, with varied histopathological patterns of inflammation and fibrosis, has been observed in individual patients with idiopathic pulmonary fibrosis. We discuss environmental factors and host response factors, such as genetic susceptibility and age, that may influence these varied manifestations. Better understanding of the mechanisms of lung repair, which include alveolar reepithelialization, myofibroblast differentiation/activation, and apoptosis, should offer more effective therapeutic options for progressive pulmonary fibrosis.

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis

“…12 Similar dramatic changes in phenotype are described for MTD occurring in the kidney, pancreas and lung indicating that a common transcriptional reprogramming process may operate to generate myofibroblasts in response to tissue injury. [2][3][4] In support of this concept there are many reports describing alterations in expression and/or activity of key transcription factors such as PPARs, NF-kB and AP-1 common to MTD of distinct organ-specific myofibroblast-precursor cells. [19][20][21][22] However, no single transcription factor or combinations of transcription factors are so far described as responsible for exerting global control of MTD.…”

“…1 Fibrosis is a disease process common to major organs such as the kidney, liver, pancreas, heart and lungs in the context of reiterative injury or infection. [2][3][4][5] Recent evidence also suggests that the stroma reaction, in which tumours benefit from the antiapoptotic and growth promoting properties of their surrounding ECM, is driven by myofibroblast secretion of collagen-rich ECM into the extracellular space surrounding the growing tumour. 6 There is therefore interest in determining the molecular events that regulate the production and behaviour of myofibroblasts during injury, infection and tumour formation.…”

“…[3][4][5][6][7] Cell transdifferentiation enables fully differentiated nonstem cells to dramatically alter their phenotype and function in a stable and long-term manner. 8 In the context of wound repair, transdifferentiation enables rapid responses to damage and injury by providing a mechanism to generate wound healing myofibroblasts from resident cells located in the vicinity of the damaged tissue.…”

“…Differentiated cells that undergo myofibroblast transdifferentiation (MTD) in response to tissue injury include hepatic stellate cells (HSC), 7 kidney mesangial cells and epithelia, 2 pancreatic stellate cells, 4 vocal fold stellate cells 9 and lung fibroblasts. 3 It is therefore likely that MTD is a generic process in wound healing responses of the majority of soft tissues. Understanding the molecular regulation of MTD should therefore provide therapeutic solutions to ineffective and aberrant wound healing responses.…”

mSmile is Necessary for Bronchial Smooth Muscle and Alveolar Myofibroblast Development

“…Asthma is a disease of airway hyper-responsiveness in which there is an increased number of BSM cells whose activity may contribute to airflow limitation (Jeffery, 2004). In pulmonary fibrosis, increased population of alveolar myofibroblasts may cause the abnormal tissue remodeling leading to increased collagen and extracellular matrix deposition that is the hallmark of this disease (Thannickal et al, 2004). The critical roles of BSM cells and alveolar myofibroblasts in both developmental and pathological processes underlie the necessity to understand the origin and developmental regulation of these essential lung mesenchymal cells.…”