| First Author | Musthafa A | Year | 2023 |
| Journal | Kobe J Med Sci | Volume | 69 |
| Issue | 3 | Pages | E96-E105 |
| PubMed ID | 37941117 | Mgi Jnum | J:358250 |
| Mgi Id | MGI:7778583 | Doi | 10.24546/0100483406 |
| Citation | Musthafa A, et al. (2023) Acute Amelioration of Inflammatory Activity Caused by Endothelin-2 Deficiency during Acute Lung Injury. Kobe J Med Sci 69(3):E96-E105 |
| abstractText | In acute lung injury (ALI), a severe insult induces a hyperinflammatory state in the lungs. The mortality rate of severe ALI remains high, and novel mechanistic insights are required to improve therapeutic strategies. Endothelin-2 (Edn2), the least studied isoform of endothelin, is involved in lung physiology and development and can be affected by various factors. One of them is inflammation, and another isoform of endothelin, endothelin-1 (Edn1), affects lung inflammatory responses. Considering the importance of Edn2 in the lungs and how Edn2 works through the same receptors as Edn1, we postulated that Edn2 may affect inflammatory responses that are central to ALI pathophysiology. In this study, we performed 24 hours intratracheal lipopolysaccharide (LPS) instillation or PBS control as an in vivo ALI model in eight-week-old conditional Edn2 knockout mice (Edn2-iKO), with Edn2-floxed mice as controls. Bronchoalveolar lavage (BAL) fluid and tissue were collected after exsanguination and analyzed for its cellular, molecular, functional, and histological inflammatory phenotypes. We found that Edn2-iKO mice displayed a reduced pro-neutrophilic inflammatory phenotype even after acute LPS treatment, shown by the reduction in the overall protein concentration and neutrophil count in bronchoalveolar lavage fluids. Further investigation revealed a reduction in mRNA interferon gamma (IFNgamma) level of Edn2-iKO lungs and suppression of its downstream signaling, including phosphorylated level of STAT1 and IL-1beta secretion, leading to reduced NFkB activation. To conclude, Edn2 deletion suppressed acute lung inflammation by reducing neutrophil-mediated IFNgamma/STAT1/IL-1beta/NFkB signaling cascade. Targeting Edn2 signaling may be beneficial for the development of novel treatment options for ALI. |
