tranilast and Acute-Lung-Injury

It has been reported that the expression of C‑X‑C motif chemokine receptor 4 (CXCR4) is increased in patients with lung injury, while CXCR4 downregulation can improve sepsis‑induced lung injury. Previous studies have shown that tranilast can inhibit CXCR4 mRNA expression. Therefore, the present study aimed to investigate whether tranilast could protect against lipopolysaccharide (LPS)‑induced lung injury via the CXCR4/Janus kinase 2 (JAK2)/STAT3 signaling pathway. A Cell Counting Kit‑8 assay was performed to evaluate the effect of different concentrations of tranilast on the viability of LPS‑induced BEAS‑2B cells. The mRNA and protein expression levels of the inflammatory factors, TNFα, IL‑1β, IL‑6, cytochrome c oxidase subunit II and inducible nitric oxide synthase were detected using reverse transcription‑quantitative PCR and western blot analysis, respectively. In addition, the cell apoptosis rate and the expression levels of apoptosis‑related proteins were analyzed using a TUNEL staining assay and western blot analysis, respectively. The expression levels of the CXCR4/JAK2/STAT3 signaling pathway‑related proteins were also determined using western blot analysis. Furthermore, the effects of tranilast on cell viability, inflammation and apoptosis were also evaluated in LPS‑stimulated BEAS‑2B cells following CXCR4 overexpression, which were pre‑treated with tranilast. The results demonstrated that tranilast could alleviate LPS‑induced cell viability, the secretion of inflammatory cytokines and cell apoptosis. In addition, cell treatment with tranilast inhibited the expression of CXCR4/JAK2/STAT3 signaling‑related proteins in LPS‑induced BEAS‑2B cells. Following CXCR4 overexpression, the alleviating effect of tranilast on cell viability, inflammatory response and apoptosis was notably attenuated. Overall, the current study suggested that tranilast could attenuate LPS‑induced lung injury via the CXCR4/JAK2/STAT3 signaling pathway, suggesting that tranilast could be considered as a promising agent for treating sepsis‑induced acute lung injury.

Topics: Acute Lung Injury; Humans; Janus Kinase 2; Lipopolysaccharides; ortho-Aminobenzoates; Receptors, CXCR4; RNA, Messenger; Sepsis; Signal Transduction; STAT3 Transcription Factor

Zhengqing Fengtongning (ZQFTN), the pharmaceutical preparation of sinomenine (SIN) derived from the medicinal plant Sinmenium acutum, is well-known in China as an effective treatment for rheumatoid arthritis (RA). However, its histamine-release anaphylactoid reactions (HRARs) occur often in some patients. Therefore, it is desirable to establish effective clinical protocols to manage such HRARs. In the study, rat models with systemic HRARs and local HRARs of the skin were established. The level of vascular permeability and mast cell numbers was determined by quantitative analysis using Evans blue dye and histological assays. The levels of histamine, leukotriene B4 (LTB4) and IL-33 in plasma were detected by UHPLC-SPE-MS, ELISA and immunohistochemistry assays, respectively. The results demonstrated that SIN significantly induced both systemic and local HRARs in rats, showing significant decrease of body temperature, increases in vascular permeability in skin, injury of lung tissues and mast cell infiltration and IL-33 expression in skin and lung tissues. Mechanistic study showed that tranilast could prevent SIN-triggered HRARs via inhibition of H1 receptor gene expression and NF-κB signaling. Our findings provide evidence that mast cell membrane stabilizers and H1 receptor blockers effectively prevent SIN-induced HRARs, and cromolyn, cetirizine and tranilast can be used in the clinic for the management of HRARs induced by ZQFTN.

Topics: Acute Lung Injury; Anaphylaxis; Animals; Anti-Allergic Agents; Cetirizine; Cromolyn Sodium; Female; Histamine; Histamine H1 Antagonists; Histamine Release; Interleukin-33; Leukotriene B4; Lung; Mast Cells; Morphinans; NF-kappa B; ortho-Aminobenzoates; Rats, Sprague-Dawley; Receptors, Histamine H1; Signal Transduction; Skin