Inhibition of P38 MAPK Downregulates the Expression of IL-1ß to Protect Lung from Acute Injury in Intestinal Ischemia Reperfusion Rats.

Acute lung injury (ALI) induced by intestinal ischemia/reperfusion (II/R) has high incidence and mortality, in which IL-1ß was essential for the full development of ALI. However, the detailed regulating mechanism for this phenomenon remains to be unclear. The purpose of this study was to investigate whether inhibition of P38 MAPK could downregulate the expression of IL-1ß to protect lung from acute injury in II/R rats. Here, we found that the level of pulmonary edema at 16 hours after operation (hpo) was obviously enhanced compared to that in 8hpo and sham groups. Immunofluorescent staining demonstrated that IL-1ß and P38 MAPK were detected in lung tissues. And rats with II/R have the highest translation level for IL-1ß and phosphorylation of P38 MAPK in lung tissues at 16hpo compared with 8hpo and sham groups. Moreover, administration of SB239063, an inhibitor of P38 α and ß, could effectively downregulate the expressions of IL-1ß and protects lung tissues from injury in II/R rats. Our findings indicate that the inhibition of P38 α and ß may downregulate the expression of IL-1ß to protect lung from acute injury in II/R, which could be used as a potential target for reducing ALI induced by II/R in the future clinical trial.

TLR4 mediates lung injury and inflammation in intestinal ischemia-reperfusion.

BACKGROUND: Splanchnic ischemia is common in critically ill patients, and it can result in injury not only of the intestine but also in distant organs, particularly in the lung. Local inflammatory changes play a pivotal role in the development of acute lung injury after intestinal ischemia, but the underlying molecular mechanisms are not fully understood. We sought to examine the role of Toll-like receptor 4 (TLR4) in the mouse model of intestinal ischemia-reperfusion (I/R)-induced lung injury and inflammation. MATERIALS AND METHODS: Adult male TLR4 mutant (C3H/HeJ) mice and TLR4 wild-type (WT) (C3H/HeOuJ) mice were subjected to 40 min of intestinal ischemia by clamping the superior mesenteric artery followed by 6 h of reperfusion. Lung histology was assessed and parameters of pulmonary microvascular permeability, inflammatory cytokine expression, and neutrophil infiltration were measured. Activation of mitogen-activated protein kinases (MAPKs) and the transcription factors nuclear factor κB (NF-κB) and activator protein-1 (AP-1) in the lungs were also detected. RESULTS: After intestinal I/R, lungs from TLR4 mutant mice demonstrated a significantly lower histological injury, a marked reduction of epithelial apoptosis associated with the decreased level of cleaved caspase-3 and the increased ratio of Bcl-xL to Bax proteins, and a large reduction in pulmonary vascular permeability and myeloperoxidase (MPO) activity in comparison with WT mice. TLR4 mutant mice also displayed marked decreases in tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) expression. Following intestinal I/R, phosporylation of p38 MAPK and activation of NF-κB and AP-1 were significantly inhibited in lung tissue from TLR4 mutant mice compared with WT controls. CONCLUSIONS: These data suggest that TLR4 plays an important role in the pathogenesis of intestinal I/R-induced acute lung injury and inflammation and that p38 kinase and NF-κB may be involved in TLR4 signaling-mediated lung inflammatory processes during intestinal I/R.

Metabolomic analysis of thermally injured and/or septic rats.

INTRODUCTION: Early diagnosis and treatment for thermal injury with septic complications continue to be a serious clinical problem. In this study, plasma biomarkers of rats in the burn and/or septic models were investigated with a metabolomic method. METHODS: Rat plasma samples were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Multivariate analysis, the principal components analysis (PCA), was used to validate metabolic changes. In addition, another multivariate method, the orthogonal partial least-squares analysis (OPLS), was used to profile potential biomarkers in models. RESULTS: Nine characteristic metabolites, including hypoxanthine, indoxyl sufate, glucuronic acid, gluconic acid, proline, uracil, nitrotyrosine, uric acid, and trihydroxy cholanoic acid were identified in models of thermal injury and/or sepsis. CONCLUSION: These biomarkers were mainly involved in oxidative stress and tissue damage, and might supply evidence for distinguishing burned septic patients from non-septic ones.