Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of the small GTPase RhoA attenuates the development of pulmonary edema and restores positive alveolar fluid clearance in a murine model of Pseudomonas aeruginosa pneumonia. Activated protein C (aPC) blocks the development of an unfavorably low ratio of small GTPase Rac1/RhoA activity in lung endothelium through endothelial protein C receptor (EPCR)/protease-activated receptor-1 (PAR-1)-dependent signaling mechanisms that include transactivating the sphingosine-1-phosphate (S1P) pathway. However, whether aPC's cytoprotective effects can attenuate the development of pulmonary edema and death associated with P. aeruginosa pneumonia in mice remains unknown. Thus, we determined whether the normalization of a depressed ratio of activated Rac1/RhoA by aPC would attenuate the P. aeruginosa-mediated increase in protein permeability across lung endothelial and alveolar epithelial barriers. Pretreatment with aPC significantly reduced P. aeruginosa-induced increases in paracellular permeability across pulmonary endothelial cell and alveolar epithelial monolayers via an inhibition of RhoA activation and a promotion of Rac1 activation that required the EPCR-PAR-1 and S1P pathways. Furthermore, pretreatment with aPC attenuated the development of pulmonary edema in a murine model of P. aeruginosa pneumonia. Finally, a cytoprotective-selective aPC mutant, aPC-5A, which lacks most of aPC's anticoagulant activity, reproduced the protective effect of wild-type aPC by attenuating the development of pulmonary edema and decreasing mortality in a murine model of P. aeruginosa pneumonia. Taken together, these results demonstrate a critical role for the cytoprotective activities of aPC in attenuating P. aeruginosa-induced lung vascular permeability and mortality, suggesting that cytoprotective-selective aPC-5A with diminished bleeding risks could attenuate the lung damage caused by P. aeruginosa in critically ill patients.
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PMID:Cytoprotective-selective activated protein C attenuates Pseudomonas aeruginosa-induced lung injury in mice. 2125 25

Pneumococcal pneumonia is a frequent cause of gram-positive sepsis and has a high mortality. The endothelial protein C receptor (EPCR) has been implicated in both the activation of protein C (PC) and the anti-inflammatory actions of activated (A)PC. The aim of this study was to determine the role of the EPCR in murine pneumococcal pneumonia and sepsis. Wild-type (WT), EPCR knockout (KO) and Tie2-EPCR mice, which overexpress EPCR on the endothelium, were infected intranasally (pneumonia) or intravenously (sepsis) with viable Streptococcus pneumoniae and euthanised at 24 or 48 hours after initiation of the infection for analyses. Pneumonia did not alter constitutive EPCR expression on pulmonary endothelium but was associated with an influx of EPCR positive neutrophils into lung tissue. In pneumococcal pneumonia EPCR KO mice demonstrated diminished bacterial growth in the lungs and dissemination to spleen and liver, reduced neutrophil recruitment to the lungs and a mitigated inflammatory response. Moreover, EPCR KO mice displayed enhanced activation of coagulation in the early phase of disease. Correspondingly, in pneumococcal sepsis EPCR KO mice showed reduced bacterial growth in lung and liver and attenuated cytokine release. Conversely, EPCR-overexpressing mice displayed higher bacterial outgrowth in lung, blood, spleen and liver in pneumococcal sepsis. In conclusion, EPCR impairs antibacterial defense in both pneumococcal pneumonia and sepsis, which is associated with an enhanced pro-inflammatory response.
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PMID:The endothelial protein C receptor impairs the antibacterial response in murine pneumococcal pneumonia and sepsis. 2440 6