Inhibition of c-Jun N-terminal Kinase Signaling Pathway Alleviates Lipopolysaccharide-induced Acute Respiratory Distress Syndrome in Rats

Abstract

Background:An acute respiratory distress syndrome (ARDS) is still one of the major challenges in critically ill patients. This study aimed to investigate the effect of inhibiting c-Jun N-terminal kinase (JNK) on ARDS in a lipopolysaccharide (LPS)-induced ARDS rat model.Methods:Thirty-six rats were randomized into three groups: control, LPS, and LPS + JNK inhibitor. Rats were sacrificed 8 h after LPS treatment. The lung edema was observed by measuring the wet-to-dry weight (W/D) ratio of the lung. The severity of pulmonary inflammation was observed by measuring myeloperoxidase (MPO) activity of lung tissue. Moreover, the neutrophils in bronchoalveolar lavage fluid (BALF) were counted to observe the airway inflammation. In addition, lung collagen accumulation was quantified by Sircol Collagen Assay. At the same time, the pulmonary histologic examination was performed, and lung injury score was achieved in all three groups.Results:MPO activity in lung tissue was found increased in rats treated with LPS comparing with that in control (1.26 ± 0.15 U in LPS vs. 0.77 ± 0.27 U in control, P < 0.05). Inhibiting JNK attenuated LPS-induced MPO activity upregulation (0.52 ± 0.12 U in LPS + JNK inhibitor vs. 1.26 ± 0.15 U in LPS, P < 0.05). Neutrophils in BALF were also found to be increased with LPS treatment, and inhibiting JNK attenuated LPS-induced neutrophils increase in BALF (255.0 ± 164.4 in LPS vs. 53 (44.5-103) in control vs. 127.0 ± 44.3 in LPS + JNK inhibitor, P < 0.05). At the same time, the lung injury score showed a reduction in LPS + JNK inhibitor group comparing with that in LPS group (13.42 ± 4.82 vs. 7.00 ± 1.83, P = 0.001). However, the lung W/D ratio and the collagen in BALF did not show any differences between LPS and LPS + JNK inhibitor group.Conclusions:Inhibiting JNK alleviated LPS-induced acute lung inflammation and had no effects on pulmonary edema and fibrosis. JNK inhibitor might be a potential therapeutic medication in ARDS, in the context of reducing lung inflammatory.

Ovarian Fibrosis

“…JNK inhibitors not only inhibit the JNK pathway but also reduce the production of oxidative stress metabolites. [ 51 ] Further in vivo studies in rats demonstrated that SP600125, a JNK inhibitor, thinned the theca cell layer, reduced interstitial collagen deposition, and attenuated inflammation. As a result, ovarian fibrosis was apparently diminished on some level.…”

Biliverdin Protects the Isolated Rat Lungs from Ischemia-reperfusion Injury via Antioxidative, Anti-inflammatory and Anti-apoptotic Effects

“…[21] Manipulation of JNK/MAPK pathway could be a potential therapeutic target for acute respiratory distress syndrome (ARDS) in the context of suppressing inflammation. [22] Western blotting results showed that, like GSH, BV treatment decreased the phosphorylation of JNK which was greatly induced in the I/R group ( P < 0.01) [Figure 3]. …”

Angiotensin-converting enzyme 2, the complement system, the kallikrein-kinin system, type-2 diabetes, interleukin-6, and their interactions regarding the complex COVID-19 pathophysiological crossroads

“…ARDS, the most severe form of ALI, 35 – 37 is a clinical syndrome of noncardiogenic pulmonary edema. 38 – 40 ARDS is characterized by an excessive inflammatory response, 41 – 43 damage to both alveolar epithelial 38 , 40 , 41 and vascular endothelial 39 , 44 , 45 cells, the subsequent breakdown of the alveolar-capillary barrier integrity, 38 , 42 , 46 impaired AFC, 40 , 41 , 45 excessive interstitial and parenchymal neutrophil migration, 38 , 43 , 45 and activation of alveolar macrophages, platelets, and pro-coagulant processes. 42 , 47 , 48 This may result in diffuse alveolar damage, 42 , 49 pulmonary fibrosis, 37 , 50 and impaired gas exchange, 42 , 51 leading to (refractory) hypoxemia 35 , 38 , 42 and possibly organ dysfunction.…”

“… 42 , 47 , 48 This may result in diffuse alveolar damage, 42 , 49 pulmonary fibrosis, 37 , 50 and impaired gas exchange, 42 , 51 leading to (refractory) hypoxemia 35 , 38 , 42 and possibly organ dysfunction. 40 , 47 , 52 …”

“…In AFC, alveolar fluid is cleared via an ENaC-mediated osmotic gradient. 40 , 41 , 63 Disruption of ENaCs can lead to impaired AFC. 42 , 62 , 64 …”