Novel mediators of idiopathic pulmonary fibrosis

Abstract

Fibrosis involving the lung may occur in many settings, including in association with known environmental agents, connective tissue diseases, and exposure to drugs or radiation therapy. The most common form is referred to as ‘idiopathic’ since a causal agent or specific association has not been determined; the strongest risk factor for idiopathic pulmonary fibrosis is aging. Emerging studies indicate that targeting certain components of aging biology may be effective in mitigating age-associated fibrosis. While transforming growth factor-β1 (TGF-β1) is a central mediator of fibrosis in almost all contexts, and across multiple organs, it is not feasible to target this canonical pathway at the ligand–receptor level due to the pleiotropic nature of its actions; importantly, its homeostatic roles as a tumor-suppressor and immune-modulator make this an imprudent strategy. However, defining targets downstream of its receptor(s) that mediate fibrogenesis, while relatively dispenable for tumor- and immune-suppressive functions may aid in developing safer and more effective therapies. In this review, we explore molecular targets that, although TGF-β1 induced/activated, may be relatively more selective in mediating tissue fibrosis. Additionally, we explore epigenetic mechanisms with global effects on the fibrogenic process, as well as metabolic pathways that regulate aging and fibrosis.

Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches

“…Generally, pulmonary fibrosis development is often preceded by acute lung inflammation, caused by viral and bacterial infections, ionizing radiation, chemotherapy, air irritants and pollutants [ 15 , 16 , 17 , 18 ], which were not resolved in time and resulted in the deposition of fibrotic tissue in the lungs and respiratory dysfunction [ 3 ]. It should be noted that the etiology of IPF is unknown and causal agent or specific association has not been determined [ 19 ], but among the many intrinsic and extrinsic risk factors, viral infections [ 20 ], gastro-esophageal reflux disease (GERD)-related micro-aspiration [ 21 ], genetic predisposition [ 22 , 23 ] are distinguished. One of the noteworthy risk factors of IPF development is GERD.…”

Pre‐clinical evidence of a dual NADPH oxidase 1/4 inhibitor (setanaxib) in liver, kidney and lung fibrosis

“…10,54 Cellular senescence is also thought to contribute to the pathology of lung fibrosis, in which senescent cells secrete senescence-associated secretory phenotype factors to promote inflammation, tissue remodelling and cell growth. 10,56,57 NOX1 is expressed in a range of pulmonary cell types, including pulmonary epithelial cells, pulmonary vascular smooth muscle cells and bronchial epithelial cells. 58 NOX4 is expressed in macrophages, smooth muscle cells, endothelial cells, mesenchymal cells and epithelial cells.…”

“…Immune cells in turn amplify inflammatory signalling and contribute to fibrosis development by exacerbating myofibroblast differentiation and ECM deposition 10,54 . Cellular senescence is also thought to contribute to the pathology of lung fibrosis, in which senescent cells secrete senescence‐associated secretory phenotype factors to promote inflammation, tissue remodelling and cell growth 10,56,57 …”

“… 10 , 53 , 54 Importantly, TGF‐β induces NOX4‐mediated ROS production in lung fibroblasts, which sustains myofibroblast differentiation and drives fibrosis progression in lung disease (Figure 4 ). 10 , 56 Injured alveolar epithelial cells also release proinflammatory mediators, which trigger the infiltration of activated immune cells to the site of injury. 10 , 54 Immune cells in turn amplify inflammatory signalling and contribute to fibrosis development by exacerbating myofibroblast differentiation and ECM deposition.…”

“… 10 , 54 Cellular senescence is also thought to contribute to the pathology of lung fibrosis, in which senescent cells secrete senescence‐associated secretory phenotype factors to promote inflammation, tissue remodelling and cell growth. 10 , 56 , 57 …”