Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophil accumulation in the lung plays a pivotal role in the pathogenesis of acute lung injury during sepsis. Directed movement of neutrophils is mediated by a group of chemoattractants, especially CXC chemokines. Local lung production of CXC chemokines is intensified during experimental sepsis induced by cecal ligation and puncture (CLP), as reflected by rising levels of MIP-2 and cytokine-induced neutrophil chemoattractant-1 in bronchoalveolar lavage fluids. Alveolar macrophages are primed and blood neutrophils are down-regulated for production of MIP-2 and cytokine-induced neutrophil chemoattractant production in response to LPS and C5a. Under these conditions of stimulation, activation of MAPKs (p38, p42/p44) occurs in sham neutrophils but not in CLP neutrophils, while under the same conditions phosphorylation of p38 and p42/p44 occurs in both sham and CLP alveolar macrophages. These data indicate that, under septic conditions, there is impaired signaling in neutrophils and enhanced signaling in alveolar macrophages, resulting in CXC chemokine production, and C5a appears to play a pivotal role in this process. As a result, CXC chemokines increase in lung, setting the stage for neutrophil accumulation in lung during sepsis.
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PMID:Divergent signaling pathways in phagocytic cells during sepsis. 1681 91

Sepsis has been associated with tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) overproduction, insulin resistance, and a profound suppression of muscle protein synthesis. However, lesser suppression of muscle protein synthesis in neonatal pigs occurs in response to endotoxin (LPS) when glucose and amino acids are provided. We hypothesize that the LPS-induced TNF-alpha and NO overproduction down-regulates insulin signaling pathway activation in neonatal pigs in the presence of fed levels of insulin, glucose, and amino acids. In skeletal muscle, inducible NOS activity was increased in response to LPS infusion, but phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1), p42/p44 mitogen-activated protein kinase (MAPK), and protein kinase B, the association of IRS-1 with phosphatidylinositol 3-kinase (PI 3-kinase), and constitutive NOS activity were not altered. In liver, activation of the insulin receptor, IRS-1, and PI 3-kinase were not affected by LPS, but p42 MAPK phosphorylation was increased. The absence of a down-regulation in the insulin signaling cascade in muscle despite the LPS-induced increase in TNF-alpha and muscle iNOS, may contribute to the near-maintenance of muscle protein synthesis rates in the presence of glucose and amino acids in LPS-infused neonatal pigs.
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PMID:Insulin signaling in skeletal muscle and liver of neonatal pigs during endotoxemia. 1859 77

The morphological and functional integrity of the microcirculation is compromised in many cardiovascular diseases such as hypertension, diabetes, stroke, and sepsis. Angiotensin converting enzyme inhibitors (ACEi), which are known to favor bradykinin (BK) bioactivity by reducing its metabolism, may have a positive impact on preventing the microvascular structural rarefaction that occurs in these diseases. Our study was designed to test the hypothesis that BK, via B2 receptors (B2R), protects the viability of the microvascular endothelium exposed to the necrotic and apoptotic cell death inducers H(2)O(2) and LPS independently of hemodynamics. Expression (RT-PCR and radioligand binding) and functional (calcium mobilization with fura-2AM, and p42/p44MAPK and Akt phosphorylation assays) experiments revealed the presence of functional B2R in pig cerebral microvascular endothelial cells (pCMVEC). In vitro results showed that the cytocidal effects of H(2)O(2) and LPS on pCMVEC were significantly decreased by a BK pretreatment (MTT and crystal violet tests, annexin-V staining/FACS analysis), which was countered by the B2R antagonist HOE 140. BK treatment coincided with enhanced expression of the cytoprotective proteins COX-2, Bcl-2, and (Cu/Zn)SOD. Ex vivo assays on rat brain explants showed that BK impeded (by approximately 40%) H(2)O(2)-induced microvascular degeneration (lectin-FITC staining). The present study proposes a novel role for BK in microvascular endothelial protection, which may be pertinent to the complex mechanism of action of ACEi explaining their long-term beneficial effects in maintaining vascular integrity.
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PMID:Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli. 1978 24

The elevated level of endothelin-1 (ET-1) has been detected in the bronchoalveolar lavage of patients with severe asthma, acute lung injury, acute respiratory distress syndrome, and sepsis. ET-1 may affect vessel tone together with lung physiology and pathology. Vascular cell adhesion molecule-1 (VCAM-1) is one kind of adhesion molecules participating in the process of polymorphonuclear leukocyte transmigration and regulating the occurrence and amplification of tissue inflammation. However, the molecular mechanisms underlying ET-1-mediated expression of VCAM-1 on human tracheal smooth muscle cells (HTSMCs) were largely unknown. Here we reported that ET-1 stimulated expression of VCAM-1 gene on HTSMCs, which was blocked by pretreatment with the inhibitors of ET receptors, Src, matrix metalloproteinases (MMPs), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatidylinositol 3-kinase (PI3K), AKT, MEK1/2, and p300, suggesting the participation of these signaling components in ET-1-regulated HTSMC responses. Furthermore, transfection with small-interfering RNA (siRNA) of Src, AKT, p42 mitogen-activated protein kinase (MAPK), or p300 downregulated the respective proteins and significantly attenuated ET-1-induced VCAM-1 expression. ET-1 also stimulated phosphorylation of Src, EGFR, PDGFR, AKT, p42/p44 MAPK, and Elk-1 and acetylation of histone H4 on HTSMCs. Immunoprecipitation assay showed the association between Elk-1 and p300 in the nucleus. Adhesion assay revealed that the adhesion of THP-1 to HTSMCs challenged with ET-1 was increased, which was attenuated by the inhibitors of ET receptors, Src, MMPs, EGFR, PDGFR, PI3K, AKT, p42/p44 MAPK, and p300. Taken together, these data suggested that ET-1 promotes occurrence and amplification of pathology-related airway inflammation via enhancing VCAM-1 expression in an ET receptor/Src/MMP/EGFR, PDGFR/PI3K/AKT/p42/p44 MAPK/Elk-1/p300 pathway in HTSMCs.
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PMID:Endothelin-1 induces VCAM-1 expression-mediated inflammation via receptor tyrosine kinases and Elk/p300 in human tracheal smooth muscle cells. 2607 54


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