Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin

Abstract

The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2−/− mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2−/− lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2−/− and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2−/− fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2−/− mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.

New developments in the biology of fibroblast growth factors

“…Spred2 is a negative regulator of the MAPK–ERK pathway and is predominantly expressed in bronchial epithelial cells. In response to bleomycin, mice lacking Spred2 show increased proliferation of bronchial epithelial cells which may contribute to the observed milder fibrosis phenotype (Kawara et al, 2020).…”

Fibrotic Idiopathic Interstitial Lung Disease: The Molecular and Cellular Key Players

“…Then, targeting the MEK pathway in fibrotic lung disease through the chemical inhibition of MEK prevented the progression of established lung fibrosis in the overexpressed TGF-α mouse model [58]. Recently, Kawara and collaborators demonstrated that Spred2 deficiency that represents an inhibitor of the rat sarcoma virus (Ras)/Rapidly Accelerated Fibrosarcoma (Raf)/MEK/ERK pathway involved in cell proliferation and inflammation, increasing the proliferation of lung epithelial cells, ameliorates pulmonary fibrosis induced by bleomycin [59]. Indeed, one of the most abundant heat shock proteins (HSPs), HSP90, that belongs to a large family of co-chaperones involved in the maintenance of proper cell protein homeostasis (proteostasis) [60], is increased in patients with IPF [61] and has recently been studied as both a biomarker of lung fibrosis and as a potential therapeutical target [62].…”

MiR-218 promotes oxidative stress and inflammatory response by inhibiting SPRED2-mediated autophagy in HG-induced HK-2 cells

“…17 The SPRED2 was identified as a novel regulator of cardiac autophagy, and its deficiency could arouse cardiac dysfunction and life-threatening arrhythmias through impaired autophagy. [18][19][20] In addition, SPRED2 affected the development of lipopolysaccharide-induced lung inflammation by negatively regulating the ERK-MAPK pathway. 21 Since SPRED2 influences diabetesrelated diseases including insulin resistance, obesity, as well as inflammation, which plays a key role in DN, it may also participate in DN process.…”