Lipoxin A4 ameliorates alveolar fluid clearance disturbance in lipopolysaccharide-induced lung injury via aquaporin 5 and MAPK signaling pathway

Abstract

Background: A characteristic of acute lung injury (ALI) is the inflammatory damage of alveolar fluid transport. Lipoxins are endogenous lipids involving in the resolution of inflammation. It is found that lipoxin A4 (LXA4) has the distinct properties to improve the anti-edema and pro-resolution function in inflammation. Since aquaporins (AQPs) have essential roles in the integrity of barrier function during fluid transport, especially AQP5 in the maintaining of the epithelium permeability, the current study is aimed to evaluate the potential role of LXA4 in regulating alveolar fluid clearance (AFC) during fluid transport and the corresponding change of AQP5 in the lung. Methods: ALI was induced by the lipopolysaccharide (LPS) intraperitoneal injection, and LXA4 treatment was given 8 hours after LPS administration. We investigated changes in the capacity of AFC, proinflammatory cytokine concentrations in bronchoalveolar lavage fluid (BALF) and the severity of ALI. Then AQP5 expression in lung tissue and potential regulatory pathways in LPS-induced ALI was explored. Results: LXA4 treatment was found to inhibit AFC capacity, inflammatory cytokine release, partially, alleviate ALI severity, and restored AQP5 expression partially. Additionally, we found that LXA4 played a protective role by the inhibition of the phosphorylation of p38 and JNK. Conclusions: In summary, our results suggest that LXA4 plays a protective role in lipopolysaccharideinduced ALI by restoring AFC capacity and upregulating AQP5 expression and inhibiting the phosphorylation of p38 and JNK. These findings suggest potential new mechanism of LXA4 as antiinflammation therapy for the impairment of alveolar fluid transport in ALI.

Therapeutic Potential of Lipoxin A4 in Chronic Inflammation: Focus on Cardiometabolic Disease

“…The LXA 4 receptor FPR2 has been identified; the properties and distribution of the receptor are known, and we are now starting to appreciate the complex intracellular signal transduction events post-LXA 4 receptor activation, which appear to be cell type-dependent. A recent study demonstrated that LXA 4 regulates the MAPK signaling pathway via inhibition of the phosphorylation of p38 and JNK in the airway . Tabas and colleagues have provided the first evidence that MerTK signaling pathways are mobilized to produce LXA 4 in macrophages .…”

“…A recent study demonstrated that LXA 4 regulates the MAPK signaling pathway via inhibition of the phosphorylation of p38 and JNK in the airway. 138 Tabas and colleagues have provided the first evidence that MerTK signaling pathways are mobilized to produce LXA 4 in macrophages. 139 In addition, 15-epi-LXA 4 suppresses PI3K/ AKT signaling pathway to regulate TNF-α-induced tissue factor in vascular endothelial cells.…”

Review of the potential of mesenchymal stem cells for the treatment of infectious diseases

“…LXA4 was found to enhance CFTR expression in AT-II cells damaged by LPS treatment through downregulation of Akt phosphorylation, which led to improved AFC[ 96 ]. LXA4 also increases the expression of α and γ subunits of ENaC channel[ 97 ], and AQP5 in LPS-stimulated epithelial cells[ 98 , 99 ], which contribute to enhanced fluid clearance, improved gas exchange, and pulmonary edema resolution during lung injury. LXA4 improves the integrity of the epithelial barrier by upregulating the expression of junction proteins such as zona occludens 1, claudin 1, and occludin[ 100 ].…”

Could aquaporin modulators be employed as prospective drugs for COVID-19 related pulmonary comorbidity?

“…Lipoxine A4 (LXA4) a braking signal in inflammatory response reduced the severity of inflammation and restored alveolar fluid clearance via upregulation of AQP5 in LPS induced lung tissue exhibiting its pro-resolution and anti- edematic activity in alleviating ALI [36] . Inhibition of NF-κB activation by fasudil a selective Rho- kinase (ROCK) inhibitor in LPS induced lung injury restored the expression of AQP5 resulting in predominant reduction in lung water content and pulmonary edema formation [37] .…”