Flufenamic acid alleviates sepsis‐induced lung injury by up‐regulating CBR1

Abstract

Investigate the effect of flufenamic acid (FFA) on lung injury of sepsis rats. Rat sepsis model was established using cecal ligation and puncture (CLP). The pathomorphology of lung tissue was detected by Hematoxylin–eosin (H&E) staining. The expression levels of tumor necrosis factor alpha (TNF‐α), interleukin‐6 (IL‐6), and high mobility group box‐1 (HMGB‐1) in serum and TNF‐α, IL‐6, malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) in lung tissues. The viability of RLE‐6TN cells was detected by CCK‐8 assay. The expression of carbonyl reductase 1 (CBR1) in RLE‐6TN cells was analyzed by Western blot analysis and reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) analysis. The inflammatory response was obviously enhanced in CLP‐constructed sepsis rats and alleviated by FFA treatment. Sepsis induced the increase of W/D ratio, promoted the levels of TNF‐α, IL‐6, HMGBR1, and MDA and inhibited the levels of SOD and GSH. FFA could effectively alleviate the sepsis‐induced lung injury. The viability of RLE‐6TN cells induced by LPS was improved with the treatment of FFA. CBR1 expression in LPS‐induced RLE‐6TN cells was decreased and FFA could up‐regulate the CBR1 expression. In addition, LPS‐induced lung injury promoted the inflammatory response in lung tissues, increased the W/D ratio and levels of TNF‐α, IL‐6, HMGBR1, and MDA while inhibited the levels of SOD and GSH. FFA could effectively improve the LPS‐induced lung injury while the effect of FFA on LPS‐induced lung injury was alleviated by CBR1 interference. FFA may alleviate sepsis‐induced lung injury by up‐regulating CBR1.

Flufenamic Acid, a Promising Agent for the Sensitization of Colistin-Resistant Gram-Negative Bacteria to Colistin

“…No previous reports have documented the antimicrobial or antibiofilm effects of FFA and colistin in combination when used to treat COL-R Gram-negative bacteria. Recent reports have documented a range of beneficial effects of FFA beyond its direct anti-inflammatory activity, including its ability to promote carbonyl reductase 1 ( CBR1 ) upregulation and thereby protect against pulmonary damage induced by sepsis ( 23 ). It can also reportedly downregulate the expression of osteoclastogenesis-related genes while activating mitogen-activated protein kinase (MAPK) signaling and thereby preventing osteoporosis ( 24 , 25 ), in addition to inducing the AMP-activated protein kinase (AMPK) activation and thereby enhancing angiogenic activity in vitro and in vivo ( 26 ).…”

Sepsis-Induced Acute Lung Injury Is Alleviated by Small Molecules from Dietary Plants via Pyroptosis Modulation

“…91 In addition, pseudoephedrine and emodin are preparations respectively made from Ephedra sinica and Rheum palmatum, the combination of which enhanced the cAMP level in lung tissue of sepsis-induced ARDs mice established by LPS injection. 92 As for directly targeting HMGB-1 in a sepsisinduced ARDs murine model, no naturally small-molecule inhibitor has been announced but precious few chemically synthesized compounds such as recombinant thrombomodulin 93 and flufenamic acid 94 were confirmed to ameliorate septic lung injury via affecting HMGB-1. As illustrated in Figure 5, in correspondence to the pyroptosis-involved pathogenesis of ARDs induced by sepsis, a class of small-molecule compounds extracted from dietary plants demonstrated remarkable beneficial effect via directly modulating the NLRP3/caspase-1/GSDMD axis in lung or via indirect ways by restraining HDAC6 or MUC1, while promoting cAMP.…”

“…In addition, pseudoephedrine and emodin are preparations respectively made from Ephedra sinica and Rheum palmatum , the combination of which enhanced the cAMP level in lung tissue of sepsis-induced ARDs mice established by LPS injection . As for directly targeting HMGB-1 in a sepsis-induced ARDs murine model, no naturally small-molecule inhibitor has been announced but precious few chemically synthesized compounds such as recombinant thrombomodulin and flufenamic acid were confirmed to ameliorate septic lung injury via affecting HMGB-1.…”

SR9009 Regulates Acute Lung Injury in Mice Induced by Sepsis

“…Sepsis, an intractable clinical syndrome, is often accompanied by multiple organ dysfunction, and the most a ected organ is the lung; thus, acute lung injury (ALI) is one of the common complications of sepsis [1,2]. What plays a core and fundamental role in sepsis-induced lung injury is the imbalance of immune response and uncontrolled in ammatory response [3].…”