Inhibition of HtrA2 alleviates inflammatory response and cell apoptosis in lipopolysaccharide‑induced acute pneumonia in rats

Abstract

Pneumonia is one of the commonest causes of death worldwide. High-temperature requirement a2 (Htra2) is a proapoptotic mitochondrial serine protease involved in caspase-dependent or caspase-independent cell apoptosis. ucF-101 (5-[5-(2-nitrophenyl) furfuryl iodine]-1,3-diphenyl-2-thiobarbituric acid), an inhibitor of Htra2, has a protective effect on organs in various diseases by inhibiting cell apoptosis. The aim of the present study was to explore whether ucF-101 has a protective effect on lungs in pneumonia. a lipopolysaccharide (lPS)-induced pneumonia model was established in rats. ucF-101 (2 µmol/kg) was used for treatment. lung injury was detected by hematoxylin and eosin staining. Pro-inflammatory cytokines and oxidative stress-related factors were detected using corresponding test kits. Tunel staining was used to measure the amount of cell apoptosis. apoptosis-associated proteins were detected by western blot assay. The present study indicated pulmonary injury induced by lPS. Treatment with ucF-101 clearly alleviated this pulmonary damage and restored the levels of pro-inflammatory cytokines and oxidative stress-related factors. in addition, ucF-101 significantly reduced lPS-induced cell apoptosis, the release of Htra2 and cytochrome from mitochondria to the cytoplasm and inhibited the expression of pro-apoptotic proteins. ucF-101 also restored the aTP level. The present results demonstrated that ucF-101 acts as a positive regulator of acute pneumonia by inhibiting inflammatory response, oxidative stress and mitochondrial apoptosis. The present study suggests ucF-101 as a potential candidate for pneumonia therapy.

Role of High-temperature Requirement Serine Protease A 2 in Rheumatoid Inflammation

“…These studies demonstrate that HtrA2 can regulate RA in part through Th17 cell differentiation of STAT3 [7]. According to one study, UCF-101 (5-[5-(2-nitrophenyl) furfuryl iodine]-1,3diphenyl-2-thiobarbituric acid), an inhibitor of HtrA2, seems to relieve pulmonary in ammation by reducing the generation of in ammatory cytokines [22]. HtrA2 de ciency has recently been shown to reduce the production of pro-in ammatory cytokines in BMDMs triggered by LPS or CpG, implying that HtrA2 is an immune response regulator [23].…”

Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation

“…These studies demonstrate that HtrA2 can regulate RA in part through the Th17 cell differentiation of STAT3 [ 7 ]. In one study, UCF-101 (5-[5-(2-nitrophenyl) furfuryl iodine]-1,3-diphenyl-2-thiobarbituric acid), which is an inhibitor of HtrA2, seems to relieve pulmonary inflammation by reducing the generation of inflammatory cytokines [ 25 ]. HtrA2 deficiency has recently been shown to reduce the production of proinflammatory cytokines in BMDMs triggered by LPS or CpG, which suggests that HtrA2 is an immune response regulator [ 26 ].…”

Mitochondrial quality control proteases and their modulation for cancer therapy

“…176 Specifically, UCF-101 alleviates acute lung injury by decreasing inflammatory response, oxidative stress, and apoptosis and may be a candidate for pneumonia treatment. 177 Furthermore, inhibition of the HTRA2/XIAP/PARP signaling pathway reduced cardiomyocyte injury. 176 In addition, UCF-101 shows protective effects against nerve injury, cerebral ischemia/reperfusion injury, traumatic spinal cord injury, kidney injury, and intestinal ischemia/ reperfusion injury by modulating oxidative stress and apoptosis.…”

“…Based on the inhibitory effect on HTRA2, UCF‐101 prevents the cell from entering apoptosis and further possesses excellent effects against injury in a variety of models 176 . Specifically, UCF‐101 alleviates acute lung injury by decreasing inflammatory response, oxidative stress, and apoptosis and may be a candidate for pneumonia treatment 177 . Furthermore, inhibition of the HTRA2/XIAP/PARP signaling pathway reduced cardiomyocyte injury 176 .…”