Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pericytes are contractile cells of the microvasculature which may contribute to the hypotension and increase in permeability that are present during inflammation and late-stage sepsis. The purpose of this study was to examine the contractile effects, if any, of septic modulators on the lung pericyte. Contractile effects were qualitatively examined using a previously developed silicone rubber method. This study further demonstrates a quantitative method for measuring the contraction of lung pericytes cultured on a collagen lattice. Contraction was measured by the change in collagen matrix area in response to vasoactive stimuli. Bradykinin and serotonin significantly increased contraction in a dose-dependent manner, with a maximum increase in contraction twice that of control. Forskolin and adenosine caused relaxation, also in a significant dose-dependent manner, with a maximum decrease in contraction of 80 and 30-40%, respectively. Histamine had no effect on contractility in either the silicone rubber or the collagen lattice assay. These results show that the lung pericyte, like the retinal pericyte, is a contractile cell and can be stimulated to contract or relax in vitro by the presence of certain inotropic agents present during inflammation and sepsis. These responses may play a role in microvascular regulation.
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PMID:Effects of vasoactive mediators on the rat lung pericyte: quantitative analysis of contraction on collagen lattice matrices. 1004 61

Proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) that are released from Kupffer cells may trigger liver inflammation and damage. Hence, endogenous mechanisms for limiting TNF-alpha expression are crucial for avoiding the development of sepsis. Such mechanisms include the anti-inflammatory actions of interleukin-10 (IL-10) as well as signaling induced by the intracellular second messenger cyclic AMP (cAMP). Kupffer cells express several receptors that activate cAMP synthesis, including E-prostanoid receptors and beta-adrenergic receptors. The expression and role of specific adenylyl cyclases in the inhibition of Kupffer cell activation have so far not been subject to study. Pretreatment of rat Kupffer cell cultures with cAMP analogues [8-(4-chlorophenyl)-thio-cAMP], adenylyl cyclase activator (forskolin), or ligands for G-coupled receptors (isoproterenol or prostaglandin E2) 30 min before the addition of lipopolysaccharide (LPS) (1 microg/ml) caused attenuated TNF-alpha levels in culture medium (forskolin/isoproterenol, P < or = 0.05; prostaglandin E2, P < or = 0.01). Forskolin also reduced IL-10 mRNA and protein (P < or = 0.05), which was not observed with the other cAMP-inducing agents. Furthermore, we found that rat Kupffer cells express high levels of the forskolin-insensitive adenylyl cyclase 9 compared to whole liver and that this expression is down-regulated by LPS (P < or = 0.05). We conclude that regulation of TNF-alpha and IL-10 in Kupffer cells depends on the mechanism by which cAMP is elevated. Forskolin and prostaglandin E2 differ in their effects, which suggests a possible role of forskolin-insensitive adenylyl cyclases like adenylyl cyclase 9.
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PMID:Effects of forskolin on Kupffer cell production of interleukin-10 and tumor necrosis factor alpha differ from those of endogenous adenylyl cyclase activators: possible role for adenylyl cyclase 9. 1623 25

Sepsis-induced vascular leakage is a major underlying cause of the respiratory dysfunction seen in severe sepsis. Here, we studied the role of MLC phosphorylation in LPS-induced endothelial hyperpermeability and assessed how the changes in phospho-MLC distribution affect LPS-induced barrier dysfunction. We demonstrated that the changes in human lung microvascular endothelial permeability are preceded by the increase in intracellular calcium level, and increase in MYPT and MLC phosphorylation. Using the siRNA approach, we showed that both LPS-induced barrier dysfunction and MLC phosphorylation are attenuated by the depletion of the smooth muscle isoform of MLC kinase (MLCK) and Rho kinase 2 (ROCK2). Surprisingly, pharmacological inhibition of both ROCK1 and 2 with Y-27632 exacerbated LPS-induced drop in transendothelial resistance, although significantly decreasing MLC phosphorylation level. We next studied the involvement of protein kinase A (PKA)-dependent pathways in LPS-induced barrier dysfunction. We showed that LPS decreased the level of PKA-dependent phosphorylation in endothelial cells; and the pretreatment with forskolin or PKA activator bnz-cAMP counteracted this effect. Forskolin and bnz-cAMP also attenuated LPS-induced increase in MLC phosphorylation level. As we have shown earlier (Bogatcheva et al., 2009), forskolin and bnz-cAMP provide protection from LPS-induced barrier dysfunction. We compared the effects of bnz-cAMP and Y-27632 on phospho-MLC distribution and observed that while bnz-cAMP increased the association of the phospho-MLC signal with the cortical structures, Y-27632 decreased this association. These data indicate that an overall decrease in MLC phosphorylation could be either beneficial or detrimental to endothelial barrier, depending on the intracellular locale of major phospho-MLC changes.
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PMID:The suppression of myosin light chain (MLC) phosphorylation during the response to lipopolysaccharide (LPS): beneficial or detrimental to endothelial barrier? 2130 11