HSF1 Attenuates LPS-Induced Acute Lung Injury in Mice by Suppressing Macrophage Infiltration.

Tao Li,Sipin Tan,Yanjuan Liu,Meidong Liu,Huafei Deng,Xueyan Shi,Jia Gu,Leijing Yin,Ke Liu,Xianzhong Xiao,Huali Zhang,Chuyi Tan,Gui Xiao,Manjit Singh Rana

doi:10.1155/2020/1936580

Abstract

Heat shock factor 1 (HSF1) is a transcription factor involved in the heat shock response and other biological processes. We have unveiled here an important role of HSF1 in acute lung injury (ALI). HSF1 knockout mice were used as a model of lipopolysaccharide- (LPS-) induced ALI. Lung damage was aggravated, and macrophage infiltration increased significantly in the bronchoalveolar lavage fluid (BALF) and lung tissue of HSF−/− mice compared with the damage observed in HSF1+/+ mice. Upon LPS stimulation, HSF−/− mice showed higher levels of monocyte chemoattractant protein-1 (MCP-1) in the serum, BALF, and lung tissue and increased the expression of MCP-1 and chemokine (C-C motif) receptor 2 (CCR2) on the surface of macrophages compared with those in HSF1+/+. Electrophoretic mobility shift assays (EMSA) and dual luciferase reporter assays revealed that HSF1 could directly bind to heat shock elements (HSE) in the promoter regions of MCP-1 and its receptor CCR2, thereby inhibiting the expression of both genes. We concluded that HSF1 attenuated LPS-induced ALI in mice by directly suppressing the transcription of MCP-1/CCR2, which in turn reduced macrophage infiltration.

Highlights

Acute lung injury is a type of acute and progressive hypoxic respiratory failure, where noncardiac pathogenic factors inside and outside the lungs cause damage to the alveolar and capillary endothelia, increasing the permeability of alveolar-capillary membrane
We found that the survival rate of the Heat shock factor 1 (HSF1)-/- + LPS group was monocyte chemoattractant protein-1 (MCP-1).1:labeled probe F: MCP-1.1: labeled probe R: MCP-1.1: competitive probe F: MCP-1.1:competitive probe R: MCP-1.1: mutant probe F: MCP-1.1: mutant probe R: MCP-1.2: labeled probe F: MCP-1.2: labeled probe R: MCP-1.2: competitive probe F: MCP-1.2:competitive probe R: MCP-1.2: mutant probe F: MCP-1.2: mutant probe R: CCR2.1:labeled probe F: CCR2.1: labeled probe R: CCR2.1:competitive probe F: CCR2.1:competitive probe R: CCR2.1: mutant probe F: CCR2.1: mutant probe R: CCR2.2: labeled probe F: CCR2.2: labeled probe R: CCR2.2: competitive probe F: CCR2.2:competitive probe R: CCR2.2:mutant probe F: CCR2.2:mutant probe R: Table 1: List of MCP-1 and CCR2 probe sequences
Combined with the relative mRNA expression level of HSF1 (Figure 3(e)), these results indicated that HSF1 played a protective role in LPS-induced acute lung injury (ALI) mice by reducing the MCP-1 expression, inhibiting macrophage infiltration

Summary

Introduction

Acute lung injury is a type of acute and progressive hypoxic respiratory failure, where noncardiac pathogenic factors inside and outside the lungs cause damage to the alveolar and capillary endothelia, increasing the permeability of alveolar-capillary membrane. Current studies indicate that inflammation is an important mechanism of ALI [2]. HSF1 is a transcription factor implicated in the heat shock response; it regulates the transcription of heat shock proteins such as Hsp, Hsp, and Hsp, which play an important cytoprotective role in lung inflammation and injury [3,4,5,6]. Our previous studies showed that HSF1 has a protective effect on LPS-induced multiorgan dysfunction syndrome [7, 8]. HSF1 reduced leukocyte infiltration into the lungs and decreased the production of several inflammatory mediators, thereby attenuating inflammatory responses and exhibiting a protective effect on endotoxemia caused by LPS. The underlying mechanisms by which HSF1 alleviates ALI need to be further explored

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