Ulinastatin protects the lungs of COPD rats through the HMGB1/TLR4 signaling pathway

Abstract

The present study aimed to investigate the protective mechanism of ulinastatin against lung injury. Rat models with chronic obstructive pulmonary disease (COPD) were used to provide guidance for the medical treatment of this disease. The rats were divided into three groups: A control group, a model group and an experimental group (each, n=10). With the exception of the control group, all of the rats were prepared as models of COPD, using the composite molding method of smoking and intratracheal instillation of lipopolysaccharide. The rats in the model group all received a conventional treatment, while the rats in the experimental group received ulinastatin. A small animal lung function detector was used to examine lung function. The forced expiratory volume/sec (FEV) was negatively correlated with the protein expression levels of Toll-like receptor 4 (TLR4) and high mobility group box protein 1 (HMGB1). Real-time fluorescence quantitative polymerase chain reaction and western blot analyses were used to detect TLR4, MyD88 (myeloid differentiation factor 88), TRAF-6 (TNF receptor-associated factor 6), LOX-1 (lectin-type oxidized LDL receptor 1) and HMGB1 mRNA, along with their protein expression levels. The lung function of rats in the model group was significantly decreased compared with in the control group (P<0.05). In the experimental group the lung function was significantly greater, when compared with in the model group; however, it remained lower than in the control group. The mRNA and protein expression levels of TLR4, MyD88, TRAF-6, LOX-1 and HMGB1 were significantly higher in the model group than in the control and experimental groups; however, levels in the experimental group were significantly higher when compared with in the control group (P<0.05). The TLR4 and HMGB1 expression levels were positively correlated in all groups, which indicated involvement of the HMGB1/TLR4 signaling pathway. The FEV was negatively correlated with the protein expression levels of TLR4 and HMGB1. Thus, the protective effect of ulinastatin in the lungs of rats with COPD is associated with changes in the HMGB1/TLR4 signaling pathway.

High‐mobility group box‐1 and inter‐alpha inhibitor proteins: In vitro binding and co‐localization in cerebral cortex after hypoxic‐ischemic injury

“…Previous studies have suggested that the light chain of IAIPs could exert its anti‐inflammatory effects by attenuating the HMGB1‐derived inflammatory cascade in adult subjects exposed to a variety of different organ‐related injury models 36‐42 . Ulinastatin (urinary trypsin inhibitor or bikunin) have been shown to attenuate lung injury in adult models secondary to chronic obstructive pulmonary disease, sepsis and lipopolysaccharide (LPS) exposure, attenuate the effects of diabetic cardiomyopathy, and reduce ischemia‐related hepatic injury and ischemia‐related forebrain injury by in part downregulating levels of HMGB1 36‐39,41,42 . Prior studies have also shown that administration of lipopolysaccharide (LPS) can stimulate the release of HMGB1 from cells of the central nervous system.…”

Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD

“…HMGB1 expression positively correlated with NF-B protein and mRNA lung levels and the elevated levels of HMGB1 were attenuated by intraperitoneally injected of a NF-B inhibitor in these animals [89]. Similarly, the elevated levels of lung HMGB1 protein and mRNA seen in LPS-exposed rats and cigarette smoke-exposed mice was attenuated by ulinastatin (100000 UI intravenously twice daily for 7 days), although the levels were not reduced to those seen in control animals [90].…”

“…These cells subsequently release others proinflammatory mediators such as TNF- and IL-1 that can consequently induce airways remodelling [79,[82][83]87]. In addition, data on animal models have shown that blocking of HMGB1 and of its intracellular pathways has a protective role in mouse models lungs, although further studies are necessary to clarify this mechanistic pathway [90].…”

<p>The Role of Toll-Like Receptors 2 and 4 in the Pathogenesis of Chronic Obstructive Pulmonary Disease</p>

“…In this way, ulinastatin inhibits the excessive release of inflammatory mediators (TNF-α, IL-6, and IL-8) and reduces lung tissue damage. 73 Zeng et al have demonstrated that sulforaphane, an isothiocyanate naturally occurring in cruciferous vegetables, exhibits an anti-inflammatory effect by inhibiting cytokine expression via the TLR2/TLR4/MyD88 signaling pathway in macrophages derived from monocytes from patients with COPD. 74 Ma et al have shown in the experimental study that Chinese herbal granules "Bufei Yishen" are effective in reducing inflammation in COPD.…”