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.