Cardiac Myocytes Activated by Septic Plasma Promote Neutrophil Transendothelial Migration

Madorin, W. Sean; Tao, Rui; Sugimoto, Naohito; Handa, Osamu; Cepinskas, Gediminas; Kvietys, Peter R.

doi:10.1161/01.res.0000124395.20249.ae

Cited by 51 publications

(52 citation statements)

References 56 publications

(64 reference statements)

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“…3B and 4) support the latter possibility; that is, AM obtained from septic mice promote PMN migration by generating PAF and H 2 O 2 , rather than chemokines/cytokines. The scenario uncovered in the present study using an in vitro construct of the pulmonary vascular-interstitial interface is markedly different from our previous in vitro studies of the myocardial vascular-interstitial interface during peritonitis (34). In the latter model, the effector cell was the cardiac myocyte, rather than AM.…”

Section: Discussioncontrasting

confidence: 70%

“…PMN were obtained from the bone marrow of the hind legs of adult mice using Percoll sedimentation and gradient centrifugation as previously described (30,34). This procedure yields 5-6 million white blood cells, 95% of which are mature PMNs (crystal violet staining).…”

Section: Cellsmentioning

confidence: 99%

“…ELISA. KC (keratinocyte-derived chemokine), LIX (LPS-inducible CXC chemokine), and TNF-␣ levels in septic plasma in the absence and presence of AM were determined by ELISA (34). Briefly, plasma samples were added to 96-well enzyme immunoassay plates coated with capture Abs (either rat anti-mouse KC or LIX mAbs, R&D System).…”

Section: Assaysmentioning

confidence: 99%

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Alveolar Macrophages from Septic Mice Promote Polymorphonuclear Leukocyte Transendothelial Migration via an Endothelial Cell Src Kinase/NADPH Oxidase Pathway

Wang

Tao

Yang

et al. 2008

The Journal of Immunology

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Alveolar macrophages (AMφ) have been implicated in the polymorphonuclear leukocyte (PMN) recruitment to the lungs during sepsis. Using an in vivo murine model of sepsis (feces in the peritoneum), we show that peritonitis leads to increased activation of AMφ and PMN migration into pulmonary alveoli. To assess cellular mechanisms, an in vitro construct of the pulmonary vascular-interstitial interface (murine AMφ, pulmonary endothelial cells, and PMN) and a chimera approach were used. Using immunologic (Abs) and genetic blockade (CXCR2-deficient AMφ), we show that CXC chemokines in septic plasma are responsible for the activation of AMφ. The activated AMφ can promote PMN transendothelial migration, even against a concentration gradient of septic plasma, by generating platelet-activating factor and H2O2. Platelet-activating factor/H2O2 induce an oxidant stress in the adjacent endothelial cells, an event that appears to be a prerequisite for PMN transendothelial migration, since PMN migration is abrogated across Cu/Zn-superoxide dismutase overexpressing endothelial cells. Using gp91-deficient endothelial cells, we show that NADPH oxidase plays an important role in the AMφ-induced PMN transendothelial migration. Pharmacologic/small interfering RNA blockade of Src kinase inhibits AMφ-induced endothelial NADPH oxidase activation and PMN migration. Collectively, our findings indicate that the PMN transendothelial migration induced by septic AMφ is dependent on the generation of superoxide in endothelial cells via the Src kinase/NADPH oxidase signaling pathway.

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Section: Discussioncontrasting

confidence: 70%

Section: Cellsmentioning

confidence: 99%

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Alveolar Macrophages from Septic Mice Promote Polymorphonuclear Leukocyte Transendothelial Migration via an Endothelial Cell Src Kinase/NADPH Oxidase Pathway

Wang

Tao

Yang

et al. 2008

The Journal of Immunology

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“…These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31).…”

Section: Alterations Of Microvasculaturementioning

confidence: 98%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

108

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Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined. Alterations of MicrovasculatureThere is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31). Cardiosuppressing Circulating Proinflammatory MediatorsAnother hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis an...

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“…ELISA was used to quantitate the concentration of the chemokines KC (keratinocyte-derived chemokine) and LIX (LPS-induced CXC chemokine) in colonic tissue, CLF, and supernatants from M⌽ as described previously (29). Samples (tissue homogenates and supernatants) were incubated with rat anti-mouse mAb directed to KC (R&D Systems), LIX (R&D Systems), and TNF-␣ (BioLegend) and Ab binding intensity measured (ExtrAvidin peroxidase staining kit; Sigma-Aldrich).…”

Section: Assaysmentioning

confidence: 99%

Points of Control Exerted along the Macrophage-Endothelial Cell-Polymorphonuclear Neutrophil Axis by PECAM-1 in the Innate Immune Response of Acute Colonic Inflammation

Sugimoto

Tao

Yang

et al. 2008

The Journal of Immunology

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PECAM-1 is expressed on endothelial cells and leukocytes. Its extracellular domain has been implicated in leukocyte diapedesis. In this study, we used PECAM-1−/− mice and relevant cells derived from them to assess the role of PECAM-1 in an experimental model of acute colonic inflammation with a predominant innate immune response, i.e., 2,4,6-trinitrobenzine sulfonic acid (TNBS). Using chimeric approaches, we addressed the points of control exerted by PECAM-1 along the macrophage-endothelial cell-polymorphonuclear neutrophil (PMN) axis. In vivo, TNBS-induced colitis was ameliorated in PECAM-1−/− mice, an event attributed to PECAM-1 on hematopoietic cells rather than to PECAM-1 on endothelial cells. The in vivo innate immune response was mimicked in vitro by using a construct of the vascular-interstitial interface, i.e., PMN transendothelial migration was induced by colonic lavage fluid (CLF) from TNBS mice or macrophages (MΦ) challenged with CLF. Using the construct, we confirmed that endothelial cell PECAM-1 does not play a role in PMN transendothelial migration. Although MΦ activation (NF-κB nuclear binding) and function (keratinocyte-derived chemokine production) induced by CLF was diminished in PECAM-1−/− MΦ, this did not affect their ability to promote PMN transendothelial migration. By contrast, PECAM-1−/− PMN did not adhere to or migrate across endothelial cell monolayers in response to CLF. Further, as compared with PECAM-1+/+ PMN, PECAM-1−/− PMN were less effective in orientating their CXCR2 receptors (polarization) in the direction of a chemotactic gradient. Collectively, our findings indicate that PECAM-1 modulation of PMN function (at a step before diapedesis) most likely contributes to the inflammation in a colitis model with a strong innate immune component.

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Cardiac Myocytes Activated by Septic Plasma Promote Neutrophil Transendothelial Migration

Cited by 51 publications

References 56 publications

Alveolar Macrophages from Septic Mice Promote Polymorphonuclear Leukocyte Transendothelial Migration via an Endothelial Cell Src Kinase/NADPH Oxidase Pathway

Alveolar Macrophages from Septic Mice Promote Polymorphonuclear Leukocyte Transendothelial Migration via an Endothelial Cell Src Kinase/NADPH Oxidase Pathway

Molecular Events in the Cardiomyopathy of Sepsis

Points of Control Exerted along the Macrophage-Endothelial Cell-Polymorphonuclear Neutrophil Axis by PECAM-1 in the Innate Immune Response of Acute Colonic Inflammation

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