Inhibition of Bruton's Tyrosine Kinase Protects Against Burn Sepsis-Induced Intestinal Injury.

Jia Wan,Fei Wang,Xu-Lin Chen,Xi Yu,Le Qiu,Jia-Qi Niu

doi:10.3389/fmed.2022.809289

Abstract

This study aimed to investigate the role and molecular mechanisms of Bruton's tyrosine kinase (BTK), a member of the Tec family in burn sepsis-induced intestinal injury. Eighty C57BL/6 mice were randomly divided into four groups: the sham group, the burn group, the burn + sepsis group, and the burn + sepsis + LFM-A13 (a selective BTK inhibitor) group. The dynamic expression profiles of BTK and p-BTK in the intestine were measured by Western blot analysis. Intestinal histopathological changes and cellular apoptosis were determined. Inflammatory cytokines in serum and intestinal tissue were examined through enzyme-linked immunosorbent assay. Myeloperoxidase (MPO) activity was determined via a colorimetric assay. Intestinal p-BTK expression in the burn+sepsis group was significantly increased compared with that in the sham and burn groups. In the burn + sepsis group, the p-BTK expression level increased over time, peaked at 12, and then decreased at 24 h. LFM-A13 administration significantly inhibited p-BTK expression in the intestine. In contrast to the sham and burn groups, the burn + sepsis group exhibited obvious histopathological changes, which gradually aggravated over time. LFM-A13 also reduced the histopathological changes and cellular apoptosis in intestinal tissues, inhibited the inflammatory cytokines IL-4, IL-6, and TNF-α in serum and intestinal tissues, and significantly inhibited the increase in intestinal MPO activity induced by burn sepsis. BTK activation is one important aspect of the signaling event that may mediate the release of the anti-inflammatory cytokine IL-4 and the pro-inflammatory cytokines IL-6 and TNF-α; oxidative stress; and intestinal cell apoptosis. Thus, it contributes to burn sepsis-induced intestinal injury.

Highlights

Burn injuries, as one of the common clinical critical illnesses worldwide caused by thermal aggressions, have caused high morbidity and mortality rates, especially in low and middle-income countries [1]
The Western blot analysis results indicated that the p-Bruton’s tyrosine kinase (BTK) level in the sham and burn groups were low, whereas that in the burn + sepsis group increased over time, peaked at 12 h, and decreased at 24 h (P < 0.05)
The burn + sepsis group demonstrated obvious histopathological changes, including glandular atrophy, epithelial thinning, and goblet cell reduction or absence that gradually aggravated over time

Summary

Introduction

As one of the common clinical critical illnesses worldwide caused by thermal aggressions, have caused high morbidity and mortality rates, especially in low and middle-income countries [1]. Burns affect the integrity of the skin, which acts as the protective organ that prevents the body from experiencing microbial invasion; extensive burn injuries are highly prone to inflicting deep damages, such as severe infections, complications, and sepsis, to the body [2]. Sepsis is a multifactorial and complex pathophysiological syndrome caused by systemic infection with exaggerated inflammatory response and leads to severe consequences, such as shock, multiple organ dysfunction, and even death [3]. A series of diagnostic and treatment measures, including appropriate antimicrobial treatment, infection control measures, fluid and nutritional support, debridement, and wound closure, have been gradually improved in recent years, considerably enhancing the prevention and treatment of burn sepsis and improving the taking rate [6, 7]. The pathogenesis and knowledge of sepsis remain insufficient even after decades of exploration by researchers, resulting in the lack of theoretical guidance for the further treatment of this disease

Objectives

Methods

Results

Conclusion