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)

The up-regulation of different adhesion molecules such as VLA-4 (CD49d/CD29) and ICAM-1 (CD54) on the pulmonary endothelium and leukocytes, is a key event in sepsis-induced lung injury leading to inflammatory tissue alterations. The value of VLA-4 and ICAM-1 as micromorphological post-mortem markers for the detection of sepsis-induced lung injury, was evaluated in a semiquantitative immunohistochemical study. VLA-4 was strongly expressed on intravascular, interstitial and intra-alveolar leukocytes in sepsis-associated fatalities, whereas in non-septic fatalities an irregular weak immunoreactivity was observed on interstitial leukocytes and no positive immunohistochemical expression was detected on intravascular or intra-alveolar leukocytes. ICAM-1 was strongly expressed on endothelial cells of the pulmonary microvasculature and on pulmonary macrophages and lymphocytes in sepsis-associated fatalities. In contrast, an infrequent weak immunohistochemical reaction for ICAM-1 was found on pulmonary endothelium and on perivascular leukocytes in non-septic fatalities. Based on the results of the present preliminary study, VLA-4 and ICAM-1 can be considered as useful immunohistochemical post-mortem markers of sepsis.
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PMID:Post-mortem markers of sepsis: an immunohistochemical study using VLA-4 (CD49d/CD29) and ICAM-1 (CD54) for the detection of sepsis-induced lung injury. 1135 15

This review addresses our present-day knowledge on the role of different cellular adhesion molecules, cytokines and glycoproteins for the detection of sepsis-induced injury in the microvasculature of the human lung using immunohistochemistry. Through the induction and modulation of endothelial cell adhesion molecules, such as E-selectin (CD 62E), the vascular endothelium controls leukocyte extravasation into tissue. E-Selectin, not expressed by unstimulated endothelium, is activated by cytokines and initiates neutrophil recruitment in sepsis-induced lung injury. Since E-selectin is strongly expressed in the pulmonary microvasculature in sepsis-associated fatalities, the immunohistochemical detection of an intense expression of E-selectin in lung tissue is a valuable diagnostic tool in the forensic postmortem elucidation of death due to sepsis. VLA-4 (CD49d/CD29) is strongly expressed on intravascular, interstitial and intra-alveolar leukocytes in sepsis-associated fatalities, whereas in non-septic fatalities an irregular weak immunoreactivity can be observed on interstitial leukocytes and no positive immunohistochemical expression can be observed on intravascular or intra-alveolar leukocytes. ICAM-1 (CD54) is strongly expressed on endothelial cells of the pulmonary microvasculature and on pulmonary macrophages and lymphocytes in sepsis-associated fatalities. In contrast, an infrequent weak immunohistochemical reaction for ICAM-1 is found on pulmonary endothelium and on perivascular leukocytes in non-septic fatalities. The up-regulation of both cellular adhesion molecules can be considered as an useful immunohistochemical postmortem marker of sepsis. Lactoferrin (LF) is an iron-binding glycoprotein located in specific (secondary) granules of leukocytes and plays a central role in the host response to infectious stimuli in providing both bacteriostatic and bactericidal protection. There is a statistically significant association between an enhanced expression of LF on pulmonary leukocytes in sepsis-related fatalities in contrast to non-septic controls. The immunohistochemical detection of an enhanced expression of LF can contribute to the postmortem discrimination between sepsis and non-septic fatalities. Application of carbohydrate-specific lectins (ConA, UEA, GSA I, GSA II, MPA, PNA, Jac, WGA, MAA, LPA, SNA) on deparaffinated lung tissue sections from sepsis-associated fatalities and control cases results to some extent in different staining patterns of alveolar epithelial cells and subepithelial seromucous glands of the bronchi. Apart from differences in binding sites for alpha-mannose, N-acetyl-neuraminic acid and alpha-(2-6)-galactose (as detected by different expression for ConA, MAA and SNA), the main finding is that no binding sites for alpha-N-acetyl-galactosamine (as investigated by MPA immunoreactivity) can be detected on alveolar epithelial cells and mucous parts of subepithelial seromucous glands in sepsis cases in contrast to the presence of such binding sites in controls. Since most intracellular pathogens persist in macrophages and epithelial cells during infection, it is likely that these pathogens contribute to a continual deprivation or consumption, respectively, of glycoproteins physiologically secreted by alveolar epithelial and glandular cells at different time points and stages of infection and may, among other mechanisms, by reducing pathogen clearance amplify the inflammatory response. Vascular endothelial growth factor (VEGF), an angiogenic and chemotactic peptide, is abundantly expressed in normal lung tissue, especially in alveolar and bronchial epithelium, glandular cells of the bronchi, and activated alveolar macrophages. Pulmonary VEGF immunostaining differs in sepsis when compared to healthy individuals. In the latter a preponderant strong VEGF immunoreaction can be found on alveolar epithelium (predominately type II pneumocytes), bronchial epithelium and glandular cells of the bronchi and bronchioli, and activated alveolar macrophages. In contrast, in sepsis no VEGF immunopositivity can beivity can be observed on bronchial epithelium or glandular cells of the bronchi and bronchioli, and no or relatively sparse VEGF immunoreactivity is found on alveolar epithelial cells. The precise mechanisms of the decreased pulmonary VEGF expression in septic patients under conditions of intensive care medicine are not clear at present. During the complex cascade of excessive pro-inflammatory and anti-inflammatory mediator release involved in the host's systemic inflammatory response in the development of sepsis-induced lung injury, VEGF expression may be suppressed in sepsis by a hitherto not identified agent or the interaction of different mediators of cellular inflammation. For the detection of sepsis-induced lung injury the aforementioned markers can be used sufficiently, e.g. to give immunohistochemical evidence of a previously undiagnosed sepsis and to confirm or rule out a presumed diagnosis of a sepsis-associated fatality. The employment of the presented immunohistochemical methods will be particularly helpful when macroscopical and routine histological autopsy findings in cases of suspected fatal sepsis are unspecific or unconvincing, respectively, and clinical data on the patient's previous history are not available. Referring to the forensic argumentation regarding causality on the subject of possibly fatal septic complications, e.g. in the sequel of diagnostic or therapeutic iatrogenic injection procedures or being relevant to pressure sore-associated fatalities, aetiopathogenetic conclusions can be optimized on the basis of the described micromorphological investigations.
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PMID:Immunohistochemical detection of sepsis-induced lung injury in human autopsy material. 1293 35

The alpha 4/beta 1 integrin very late antigen-4 (CD49d/CD29) is up-regulated on circulating neutrophils of septic patients. Although no individual agent mimics this effect of sepsis, we now report that following priming of human neutrophils with lipopolysaccharide or tumor necrosis factor alpha (TNF-alpha), addition of formyl-Met-Leu-Phe (fMLP) results in a "stimulated", sepsis-like, four- to fivefold rise in CD49d expression. TNF/fMLP stimulation also produced a similar increase in CD49d-mediated adhesion of neutrophils to a vascular cell adhesion molecule-1 (VCAM-1)-coated surface. Adenosine is a naturally occurring, anti-inflammatory mediator released from injured or inflamed tissues. We observed that stimulated neutrophil CD49d expression was decreased by activation of A(2A) adenosine receptors (A(2A)AR) with the selective agonist 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylicacid methyl ester (ATL146e; EC(50)=6.4 nM). ATL146e (100 nM) also reduced the fraction of stimulated neutrophils that adhered to VCAM-1 from 38 +/- 6% to 27 +/- 5%. Inhibition of CD49d expression was equally inhibited by ATL146e, added before or after TNF priming, and was reversed by incubation with the A(2A)AR-selective antagonist 4-[2-[7-amino-2-(2-furyl) (1, 2, 4)triazolo(2,3-a) (1, 3, 5)triazin-5-yl-amino]ethyl]-phenol (ZM241385; 100 nM). A suboptimal ATL146e concentration (1 nM) combined with the type IV phosphodiesterase inhibitor rolipram (100 nM) synergistically decreased stimulated CD49d expression by >50%. The cyclic adenosine monophosphate (cAMP)-dependent kinase [protein kinase A (PKA)] inhibitor H-89 (10 microM) reversed the effect of ATL146e on stimulated CD49d expression. Other means of increasing cAMP in neutrophils also decreased stimulated CD49d expression. We conclude that adenosine binding to A(2A)AR counteracts stimulation of neutrophil CD49d integrin expression and neutrophil binding to VCAM-1 via a cAMP/PKA-mediated pathway.
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PMID:Activation of A2A adenosine receptors inhibits expression of alpha 4/beta 1 integrin (very late antigen-4) on stimulated human neutrophils. 1452 68

An excessive interaction of blood neutrophils with microvascular walls may underlie the organ failure of sepsis. In this study, flow cytometric analysis was used to investigate whether plasma from 22 patients with sepsis altered the expression of the adhesion molecules (CD11a, CD11b, CD49d, and CD62L) on normal blood neutrophils and enhanced their binding to cultured endothelium. Most of the plasma samples from patients with sepsis increased the percentage of neutrophils bearing CD49d (86% samples versus 22% normal plasma samples; P < 0.001) and CD64 (69% samples versus 17% normal plasma samples; P < 0.001). This effect was not seen with plasma from patients with community-acquired infections who did not develop sepsis, nor with plasma from patients with acute or chronic inflammation who had no evidence of infection. A direct association was noted between the percentage of neutrophils expressing CD64 in the blood of patients with sepsis and the ability of plasma from these patients to up-regulate CD64 on normal neutrophils. Although CD62L was present on the majority of neutrophils after incubation with sepsis plasma, it was less apparent when the cells were cultured with normal plasma. The patients' plasma had no effect on neutrophils expressing CD11a and CD11b. High levels of TNF-alpha, IL-6, IL-8, and IL-10 were detected in the patients' blood, but incubation of the recombinant forms of these cytokines with neutrophils, even in the presence of LPS, did not increase CD49d and CD64 expression. The sepsis plasma also enhanced the attachment of neutrophils to untreated and TNF-alpha-treated endothelium, and this binding was impeded by anti-CD49d and anti-CD64 antibodies. We suggest that changes in the phenotype of neutrophils by circulating factors may facilitate their attachment to endothelium, which may be an important factor in the induction of organ dysfunction in severe sepsis.
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PMID:Plasma from patients with sepsis up-regulates the expression of CD49d and CD64 on blood neutrophils. 1901 Nov 62

Endothelial activation is pivotal in the development and escalation of sepsis. Central to endothelial activation is the endothelial up-regulation of cellular adhesion molecules (CAMs) including E-selectin, ICAM-1, VCAM-1, and PECAM-1. Shed CAMs are also found in circulating soluble forms (sCAMs). We investigated whether sCAMs can be used as biomarkers for the differentiation between septic and non-septic patients. Furthermore, we investigated lymphocyte and monocyte expression of LFA-1 (CD11a/CD18) and VLA-4 (CD49d/CD29) ligands for ICAM-1 and VCAM-1, respectively. Twenty-one septic and 15 critically ill non-septic patients were included. All patients had an APACHE II score above 13 at ICU admission. Fifteen healthy volunteers served as controls. Flow cytometry was used to estimate levels of sE-selectin, sICAM-1, sVCAM-1, sPECAM-1, and the cellular expression of CD11a and CD49d. Levels of sE-selectin, sICAM-1 and sPECAM-1 were higher in the septic patients compared with the non-septic patients and controls at admission and during the observation period. Lymphocyte and monocyte expression of CD11a and CD49d was suppressed or unaltered in the septic patients compared with the non-septic patients and controls. Levels of sE-selectin, sICAM-1, and sPECAM-1 were able to discriminate between septic and non-septic patients, indicating that sCAMs may be potential diagnostic biomarkers of sepsis.
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PMID:The use of the soluble adhesion molecules sE-selectin, sICAM-1, sVCAM-1, sPECAM-1 and their ligands CD11a and CD49d as diagnostic and prognostic biomarkers in septic and critically ill non-septic ICU patients. 2753 81

Neutrophil migration to the site of bacterial infection is a critical step in host defense. Exclusively produced in the bone marrow, neutrophil release into the blood is tightly controlled. Although the chemokine CXCL1 induces neutrophil influx during bacterial infections, its role in regulating neutrophil recruitment, granulopoiesis, and neutrophil mobilization in response to lung infection-induced sepsis is unclear. Here, we used a murine model of intrapulmonary Streptococcus pneumoniae infection to investigate the role of CXCL1 in host defense, granulopoiesis, and neutrophil mobilization. Our results demonstrate that CXCL1 augments neutrophil influx to control bacterial growth in the lungs, as well as bacterial dissemination, resulting in improved host survival. This was shown in Cxcl1 -/- mice, which exhibited defective amplification of early neutrophil precursors in granulocytic compartments, and CD62L- and CD49d-dependent neutrophil release from the marrow. Administration of recombinant CXCL2 and CXCL5 after infection rescues the impairments in neutrophil-dependent host defense in Cxcl1 -/- mice. Taken together, these findings identify CXCL1 as a central player in host defense, granulopoiesis, and mobilization of neutrophils during Gram-positive bacterial pneumonia-induced sepsis.
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PMID:CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3. 3072 78