Shock/Sepsis/Trauma/Critical CareBML-111 attenuates acute lung injury in endotoxemic mice
Introduction
Acute lung injury (ALI), or acute respiratory distress syndrome, is a clinical syndrome associated with respiratory dysfunction. It is a complication of sepsis and has a ∼50% mortality rate [1]. The administration of lipopolysaccharide (LPS), a gram-negative bacterial endotoxin, has been used as a model of sepsis-related lung injury in different studies [2], [3].
The endothelium plays a critical role in the pathophysiology of systemic inflammation, regulating cellular trafficking, maintaining blood fluidity, contributing to the local balance in pro- and anti-inflammatory mediators, participating in generation of new blood vessels, and undergoing programmed cell death [4]. The importance of endothelial barriers, which separate blood and air in the lung and increase vascular permeability in pulmonary edema, in ALI has been well established [5]. Endothelial cell junctions present a particularly complex network of adhesion proteins that are linked to the intracellular cytoskeleton and signaling partners. These proteins are organized into distinct structures called tight junctions (TJs) and adherens junctions (AJs) [6]. Defects in the organization of endothelial cell junctions are associated with many disease pathologies, such as vascular malformations, hemorrhage, and tissue edema. Thus, maintaining the endothelial cell junctions would be an effective therapeutic strategy for ALI in endotoxemic mice.
Lipoxins (LXs) are the first recognized lipid mediators. They have unique structures that are derived from arachidonic acid and dual anti-inflammatory and proresolution activities [7]. Proresolving mediators, such as LX and maresin 1, have been demonstrated to have protective effects in many inflammatory and organ-specific disease models, such as brain ischemia–reperfusion injury [8], [9], colitis [10], ALI [11], asthma [12], and so on. BML-111 (Fig. 1) is a stable biosynthesized agonist of the LXs receptor (formyl peptide receptor-2) [13] and displays proresolving and anti-inflammatory effects in carbon tetrachloride–induced liver injury [14], hemorrhagic shock–induced ALI [15], and ventilator-induced lung injury [16].
However, the protective effects of BML-111 in lung injury in a mouse model of endotoxemia remain unknown. To elucidate these effects, we carried out the present study with the hypothesis that BML-111 would mitigate lung injury in endotoxemic mice and alleviate endothelial hyperpermeability in vitro.
Section snippets
Animals
Two hundred male C57BL/6 mice (8–10-wk-old, 20–25 g) were purchased from Wuhan University Laboratory Center (Wuhan, China). All the animal experiments were approved by the Animal Care and Use Committee of Tongji Medical College of Huazhong University of Science and Technology. All the animal studies have been reported in accordance with the animal research: reporting in vivo experiments guidelines for reporting experiments involving animals [17]. Mice were maintained in a pathogen-free room.
BML-111 improved the survival rate and maintained the body weight
The severity of endotoxemia in this mouse model was evaluated by measuring the survival rate and rate of body weight loss. As shown in Figure 2A, the survival rate in the Control and BML-111 group was 100% at day 7. The mice in the BML-111 + LPS group had a lower survival rate at 37.5% compared with the mice in the LPS and Boc-2 groups, which displayed 0% survival at day 2 and day 3, respectively. Compared with the Control group, the body weight of the mice in the LPS group was significantly
Discussion
Female mice express a higher level of estrogen than male mice, and estrogen exerts a lung protection effect in different lung injury models [21], [22]. To eliminate the effect of estrogen and focus on the potential effect of BML-111 in this study, we chose a model of ALI in endotoxemic male mice. Our findings indicate that the administration of BML-111 in endotoxemic mice significantly prolonged survival, attenuated the histologic damage of the lung, reduced pulmonary proinflammatory cytokines
Conclusions
In summary, our findings demonstrated that BML-111 attenuated lung injury and alleviated endothelial hyperpermeability by upregulating the expression of endothelial cell junction proteins. The pretreatment of BML-111 in this study restricts its clinical translation, but our data still indicated that BML-111 could be a useful chemical reagent for the development of a new therapy for treating LPS-induced ALI.
Acknowledgment
This study was supported by grants from the National Natural Science Foundation of China (no. 30930089, 81372036, 81171790) and Key Clinical Project of Ministry of Health of China (2012-47).
Authors' contributions: M.T. and L.C. performed the research and wrote the article. B.L. and Y.W. made substantial contributions to the animal experiment. S.L. and A.W. performed the in vitro study and analyzed the data. S.Y. and Y.S. designed the experiment and revised the article.
References (35)
- et al.
Lipopolysaccharide-induced lung injury in mice. II. Evaluation of functional damage in isolated parenchyma strips
Pulm Pharmacol Ther
(2000) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome
Blood
(2003)- et al.
Endothelial pathomechanisms in acute lung injury
Vascul Pharmacol
(2008) - et al.
Lipoxin A4 analogue protects brain and reduces inflammation in a rat model of focal cerebral ischemia reperfusion
Brain Res
(2010) - et al.
Protective effects of BML-111, a lipoxin A(4) receptor agonist, on carbon tetrachloride-induced liver injury in mice
Hepatol Res
(2007) - et al.
BML-111, a lipoxin receptor agonist, protects haemorrhagic shock-induced acute lung injury in rats
Resuscitation
(2012) - et al.
Erythropoietin attenuates lung injury in lipopolysaccharide treated rats
J Surg Res
(2009) - et al.
Akt pathway is required for oestrogen-mediated attenuation of lung injury in a rodent model of cerulein-induced acute pancreatitis
Injury
(2011) - et al.
Role of Akt/HO-1 pathway in estrogen-mediated attenuation of trauma-hemorrhage-induced lung injury
J Surg Res
(2013) - et al.
Endothelial cell junctions and the regulation of vascular permeability and leukocyte transmigration
J Thromb Haemost
(2008)
Annexin 2 regulates endothelial morphogenesis by controlling AKT activation and junctional integrity
J Biol Chem
One-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome
Intensive Care Med
Endothelin-receptor gene-expression in rat endotoxemia
Intensive Care Med
The role of adherens junctions and VE-cadherin in the control of vascular permeability
J Cell Sci
Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators
Nat Rev Immunol
A lipoxin A4 analog ameliorates blood-brain barrier dysfunction and reduces MMP-9 expression in a rat model of focal cerebral ischemia-reperfusion injury
J Mol Neurosci
A beta-oxidation-resistant lipoxin A4 analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction
Proc Natl Acad Sci U S A
Cited by (21)
Development and characterization of a novel, megakaryocyte NF-κB reporter cell line for investigating inflammatory responses
2021, Journal of Thrombosis and HaemostasisBML-111, a lipoxin receptor agonist, protects against acute injury via regulating the renin angiotensin-aldosterone system
2019, Prostaglandins and Other Lipid MediatorsCitation Excerpt :BML-111 (5(S), 6(R),7-trihydroxy-heptanoic acid methylester), a Lipoxin receptor agonist, is a commonly used LXs analogue initially shown to be equiactive with LXA4 with respect to inhibition of LTB4-induced neutrophil migration [35]. Subsequent studies suggest potent anti-inflammatory properties of BML-111 in numerous diseases, including acute lung injury [36,37], acute liver injury [38,37–39], arthritis [40], sepsis [41], ischemia/reperfusion injury [42], and ischemic stroke [43], hepatic fibrosis [28], and hepatocellular carcinoma [29,30]. Here, we used BML-111 to mimic the effects of LXs which are highly expressed in liver and lung.
BML-111 alleviates acute lung injury through regulating the expression of lncRNA MALAT1
2018, Archives of Biochemistry and BiophysicsCitation Excerpt :The potential mechanism underlying BML-111 alleviated lung injury has been reported by previous study. For example, Tang et al. reported that BML-111 attenuated lung injury rats that induced by LPS by upregulating the binding proteins and further decreasing the hypertonicity in endothelium [12]. BML-111 could decrease the inflammatory infiltration and promoted the expression of IκB-α and NF-κB p65 and further fade the inflammatory response in rats lung injury that induced by hemorrhagic shock [13].
BML-111 equilibrated ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas axis to protect hepatic fibrosis in rats
2017, Prostaglandins and Other Lipid MediatorsCitation Excerpt :Because native LXs are chemically labile and undergo inactivation in vivo through either dehydrogenation and/or omega-oxidation (depending on the local environment) [25], many stable analogs have been synthesized and extensively used. BML-111(5(S), 6(R), 7-trihydroxyheptanoic acid methyl ester) was the most typical biosynthesized agonist of the LXs receptor, and displayed strong anti-inflammatory and pro-resolution functions in many kinds of organs and diseases [5,6,26–31]. In this paper, BML-111 was used to mimic the effects of LXs also.
iRhom2 is involved in lipopolysaccharide-induced cardiac injury in vivo and in vitro through regulating inflammation response
2017, Biomedicine and PharmacotherapyCitation Excerpt :Pathological studies have shown that inflammation response is one of the most common underlying molecular and cellular pathophysiologies of heart injury [4]. Lipopolysaccharide (LPS) is a major constituent of the bacterial outer membrane, and serves a crucial function in the initiation of the pathophysiological cascades [5,6]. A reduction in LPS has been associated with improved outcomes in patients with heart disease [7].
Overexpression of FoxM1 optimizes the therapeutic effect of bone marrow mesenchymal stem cells on acute respiratory distress syndrome
2023, Stem Cell Research and Therapy
M.T. and L.C. made equal contribution to this work.