Abstract
Liver ischemia and reperfusion (I/R) induce local and distant tissue injuries, contributing to morbidity and mortality in a wider range of pathologies. This is especially seen under uncontrolled aseptic inflammatory conditions, leading to injury of remote organs, such as lung injury, and even failure. Saquinavir (SQV) is a kind of HIV protease inhibitor that possesses an anti-inflammatory property. In this study, we investigated whether SQV suppresses Toll-like receptor 4- (TLR4-) dependent signaling pathways of high-mobility group box 1 (HMGB1) and P38/JNK, conferring protection against murine liver I/R-induced lung injury. To investigate our hypothesis, C57BL/6 mice and TLR4 knockout mice (TLR4−/−) were used to perform the study. SQV administration markedly attenuated remote lung tissue injury after 1-hour ischemia and 6-hour reperfusion of the liver. To our expectation, SQV attenuated I/R-induced lung edema, hyperpermeability, and pathological injury. The beneficial effects of SQV were associated with decreased levels of circulating and lung tissue inflammatory cytokines, such as IL-6, IL-1β, TNF-α, and iNOS. The protective effect of SQV was also associated with decreased lung tissue expression of HMGB1, TLR-4, and p-P38/JNK, but not p-ERK in wild-type liver I/R mice. Overall, this study demonstrated a new role of SQV, facilitating negative regulation of HMGB1- and P38/JNK-mediated TLR-4-dependent signaling pathways, conferring protection against liver I/R-induced lung injury.
Highlights
Liver ischemia and reperfusion (I/R) causes systematic sterile inflammation that damages the local organ itself and led to uncontrolled systemic inflammation, resulting in remote organ injury and morbidity [1,2,3]
High-mobility group box1 (HMGB1) has been identified as an endogenous TLR4 ligand [15, 16] and evidences suggest that HMGB1TLR4 activation can lead to immunopathological disorders in the acute state, such as I/R [10], hemorrhagic shock [17], and trauma [18]
We explored whether SQV could protect lung inflammation and injury induced by liver I/R via the TLR4/ HMGB1 signaling pathway
Summary
Liver I/R causes systematic sterile inflammation that damages the local organ itself and led to uncontrolled systemic inflammation, resulting in remote organ injury and morbidity [1,2,3]. Several studies have reported that the lungs are susceptible to damage during liver I/R [4, 5]. We [9] and others [10,11,12] have identified that TLR4 plays an indispensable role in the liver I/R injury. High-mobility group box (HMGB1) is originally discovered as a nuclear protein that is released to the cytosol and even extracellular space in response to specific conditions [13, 14]. Mitogen-activated protein kinases (MAPKs) are signaling components that significantly convert extracellular stimuli into cellular responses [19, 20]. Studies have demonstrated that HMGB1 regulates inflammatory responses through MAPK signaling pathways [14, 19]
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