3.4 Necroptosis in pulmonary fibrosis
Idiopathic pulmonary fibrosis(IPF) is a chronic, progressive, and fibrotic lung disease which characterized by multiple genetic and environmental risk factors that cause micro-damage to the aging alveolar epithelial cells, in turn, leads to abnormal communication of epithelial-fibroblast, induces excessive deposition of ECM which produced by myofibroblasts and lung interstitial remodeling, ultimately leads to the destruction of alveolar structure, reduced lung compliance, interruption of gas exchange, until respiratory failure and death (Richeldi, Collard and Jones 2017). Evidences show that RIPK3 and p-MLKL levels in the lungs of IPF patients are obviously higher than those in healthy lungs. RIPK3 deficient mice could efficiently restrain the (damage associated molecular pattern) DAMP releasing, cell demise, and lung fibrosis which manifests that core components of necroptosis may be a specific target in the treatment of IPF (Lee et al. 2018). Acute lung injury (ALI), one of the most common complications in severe patients (Rubenfeld et al. 2005), is results in early inflammation, respiratory distress, and later fibrosis (Cui et al. 2019). Mice experiment indicate that RIP3-mediated necroptosis in hypoxia-induced lung injury neonatal mice, which can be improved by knockout of RIPK3 (Syed et al. 2019). Moreover, significant increases of necroptosis components were observed in the lungs of ALI mice induced by lipopolysaccharide (LPS). GSK872, a RIPK3 inhibitor can obviously restrained the activation of necroptosis and amelioration of lung injury (Chen et al. 2018b). In patients requiring ventilator support, mechanical ventilation may induce ALI (ventilator-induced lung injury, VILI). Interestingly, in clinical studies, researchers discovered that RIPK3 was increased in patients with mechanical ventilation. Moreover, RIPK3 deficiency mice were protected from VILI (Siempos et al. 2018). Present studies indicate that necroptosis have an important role in ALI and lung fibrosis.
Inhibit the key proteins of necroptosis may improve acute and chronic lung diseases.