Involvement of Alveolar Epithelial Cell Necroptosis in Idiopathic Pulmonary Fibrosis Pathogenesis

Abstract

Alveolar epithelial cell (AEC) injury leading to cell death is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF). Among regulated/programmed cell death, the excessive apoptosis of AECs has been widely implicated in IPF pathogenesis. Necroptosis is a type of regulated/programmed necrosis. A multiprotein complex composed of receptor-interacting protein kinase (RIPK)-1 and -3 plays a key regulatory role in initiating necroptosis. Although necroptosis participates in disease pathogeneses through the release of damage-associated molecular patterns, its association with IPF progression remains elusive. In this study, we attempted to illuminate the involvement of RIPK3-regulated necroptosis in IPF pathogenesis. IPF lung tissues were used to detect necroptosis, and the role of RIPK3 was determined using cell culturing models of AECs. Lung fibrosis models of bleomycin (BLM) treatment were also used. RIPK3 expression levels were increased in IPF lungs, and both apoptosis and necroptosis were detected mainly in AECs. Necrostatin-1 and RIPK3 knockout experiments in AECs revealed the participation of necroptosis in BLM and hydrogen peroxide-induced cell death. BLM treatment induced RIPK3 expression in AECs and increased high-mobility group box 1 and IL-1β levels in mouse lungs. The efficient attenuation of BLM-induced lung inflammation and fibrosis was determined in RIPK3 knockout mice and by necrostatin-1 with a concomitant reduction in high-mobility group box 1 and IL-1β. RIPK3-regulated necroptosis in AECs is involved in the mechanism of lung fibrosis development through the release of damage-associated molecular patterns as part of the pathogenic sequence of IPF.

Necroptosis: a crucial pathogenic mediator of human disease

“…Ripk3 deficiency and necrostatin-1 reduced lung inflammation and DAMP (i.e., HMGB1, IL-1β) release in response to BLM. Thus, necroptosis activation in AECs and release of necrotic DAMPs may participate in pulmonary fibrogenesis (97).…”

Cell Death in the Lung: The Apoptosis–Necroptosis Axis

“…Recently, alveolar epithelial cell death has been suggested to occur via necroptosis in IPF. RIPK3 expression is increased in IPF alveolar epithelial cells, and Ripk3 -deficient mice have attenuated fibrosis and decreased HMGB1 in a bleomycin model of IPF (127).…”

Toll interacting protein protects bronchial epithelial cells from bleomycin‐induced apoptosis

“…2 Bleomycin is a widely used experimental agent associated with lung epithelial cell injury, death, and fibrosis. [35][36][37][38] Bleomycin treatment of primary HBE cells isolated from human donor lungs induced cell death as measured with TUNEL staining ( Figure 3A). Overexpressing a TOLLIP-V5 fusion protein in these cells reduced TUNEL+ cells by 42% ( Figure 3A,B).…”