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Christopher D Raeburn

Publications and source records attributed to Christopher D Raeburn.

16 recordsLinked to original sources
PubMed2004

Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and p55 TNF-alpha receptor.

Hemorrhagic shock causes myocardial contractile depression. Although this myocardial disorder is associated with increased expression of tumor necrosis factor-alpha (TNF-alpha), the role of TNF-alpha as a myocardial depressant factor in hemorrhagic shock remains to be determined. Moreover, it is unclear which TNF-alpha receptor mediates the myocardial depressive effects of TNF-alpha. Toll-like receptor 4 (TLR4) regulates cellular expression of proinflammatory mediators following lipopolysaccharide stimulation and may be involved in the tissue inflammatory response to injury. The contribution of TLR4 signaling to tissue TNF-alpha response to hemorrhagic shock and TLR4's role in myocardial depression during hemorrhagic shock are presently unknown. We examined the relationship of TNF-alpha production to myocardial depression in a mouse model of nonresuscitated hemorrhagic shock, assessed the influence of TLR4 mutation, resulting in defective signaling, on TNF-alpha production and myocardial depression, and determined the roles of TNF-alpha and TNF-alpha receptors in myocardial depression using a gene knockout (KO) approach. Hemorrhagic shock resulted in increased plasma and myocardial TNF-alpha (4.9- and 4.5-fold, respectively) at 30 min and induced myocardial contractile depression at 4 h. TLR4 mutation abolished the TNF-alpha response and attenuated myocardial depression (left ventricular developed pressure of 43.0 +/- 6.2 mmHg in TLR4 mutant vs. 30.0 +/- 3.6 mmHg in wild type, P < 0.05). TNF-alpha KO also attenuated myocardial depression in hemorrhagic shock, and the p55 receptor KO, but not the p75 receptor KO, mimicked the effect of TNF-alpha KO. The results suggest that TLR4 plays a novel role in signaling to the TNF-alpha response during hemorrhagic shock and that TNF-alpha through the p55 receptor activates a pathway leading to myocardial depression. Thus TLR4 and the p55 TNF-alpha receptor represent therapeutic targets for preservation of cardiac mechanical function during hemorrhagic shock.

Animals↗
PubMed2004

Interleukin-10 attenuates the response to vascular injury.

BACKGROUND: The inflammatory response to vascular injury is characterized by expression of cytokines, growth factors, and chemokines that conspire to promote vessel remodeling and intimal hyperplasia (IH). Interleukin-10 (IL-10) is a multifunctional cytokine that has several anti-inflammatory properties in vitro. Few studies have evaluated the effects of IL-10 in experimental atherosclerosis. The purpose of the present study was to determine the influence of IL-10 on vascular inflammation and IH following mechanical injury. METHODS: Wire carotid injury was performed in wild-type (WT) mice with and without IL-10 treatment. Immunohistochemistry, PCR, and ELISA assays were used to examine vessel production of basic fibroblast growth factor (bFGF), monocyte chemotactic protein-1 (MCP-1), and nuclear factor kappa B (NFkappaB). Vessels were morphometrically analyzed for IH. RESULTS: Carotid injury induced early expression of MCP-1 and bFGF that was abrogated in mice treated with IL-10. Similarly, injury-induced expression of NFkappaB message and protein was attenuated in mice receiving exogenous IL-10. Compared to untreated mice, IL-10 markedly decreased levels of IH. Interestingly, carotid injury in IL-10-deficient mice resulted in an augmented IH response compared to injured WT mice. CONCLUSIONS: In an in vivo model of direct vascular injury, IL-10 decreased expression of the pro-inflammatory transcription factor, NFkappaB, and the mitogenic chemokine and growth factor, MCP-1 and bFGF, respectively. These observations were associated with IL-10-induced attenuation of IH. Furthermore, endogenous IL-10 appeared to suppress the injury response. In conclusion, exogenously delivered IL-10 may represent a clinically relevant anti-inflammatory strategy for post-injury intimal hyperplasia.

Animals↗
PubMed2003

[A low level of TNF-mediates hemorrhage-induced acute lung injury via p55 TNF receptor].

OBJECTIVE: To examine the temporal relationship of pulmonary TNF-alpha production to acute lung injury (ALI) during hemorrhagic shock (HS). METHODS: HS was induced in mice by removal of 30% of calculated total blood volume. Lung TNF-alpha was measured by ELISA. Lung neutrophil accumulation was detected by immunofluorescent staining, and pulmonary microvascular permeability was assessed using Evans blue dye. RESULTS: While HS induced a slight and transient increase in lung TNF-alpha, neutrophil accumulation preceded the change in lung TNF-alpha. However, lung neutrophil accumulation and the increase in microvascular permeability were abrogated in TNF-alpha knockout mice, and both were restored by administration of low dose TNF-alpha to TNF-alpha knockout mice prior to HS. Both neutrophil accumulation and microvascular leak were abrogated in p55 TNF-alpha receptor knockout mice, while p75 TNF-alpha receptor knockout mice behaved similar to wild type. CONCLUSION: A low level of pulmonary TNF-alpha is sufficient to mediate HS-induced acute lung injury and that the p55 TNF-alpha receptor plays a dominant role in regulating the pulmonary inflammatory response to HS. The results suggest that anti-TNF-alpha strategies for the control of the pulmonary inflammatory response to HS can be directed toward antagonizing the p55 TNF-alpha receptor.

Animals↗
PubMed2003

Diagnostic implications of C-reactive protein.

An elevated level of C-reactive protein (CRP), an acute phase protein, is one of many downstream indicators of inflammation. Physiologically, CRP enhances cell-mediated immunity by promoting phagocytosis, accelerating chemotaxis, and activating platelets. The purposes of this article are (1) to review the clinical data implicating serum CRP level as a systemic marker of focal inflammation and (2) to explore serum CRP level as a reflection of the inflammatory component of atherogenesis. Our findings indicate that CRP levels serve as an early marker of the magnitude of inflammation in events as dissimilar as appendicitis and myocardial infarction. The level of circulating CRP correlates with endovascular disease and may serve to identify otherwise asymptomatic patients at sufficient cardiovascular risk to warrant aggressive therapy. Determining whether CRP has a direct pathologic role in the vascular wall itself may have the most clinical relevance.

Arteriosclerosis↗
PubMed2002

Toll-like receptor-4 signaling mediates pulmonary neutrophil sequestration in response to gram-positive bacterial enterotoxin.

BACKGROUND: Toll-like receptors (TLRs) serve as mediators of innate immune responses to pathogen-associated molecular patterns (PAMPs) which include lipopolysaccharide (LPS) and staphylococcal enterotoxin B (SEB). TLR-4 is thought to act as the primary effector of LPS recognition and TLR-2 is thought to mediate responses to Gram-positive bacterial proteins. Chemokines such as macrophage inflammatory protein (MIP-2) are peptides that are responsible for lung neutrophil (PMN) sequestration following an infectious or inflammatory insult. Given the Gram-positive origin of SEB, we hypothesized that mice with altered TLR-4 signaling would exhibit no difference in lung PMN sequestration following SEB when compared to wild-type mice. METHODS: Wild-type and TLR-4 mutant mice were administered intratracheal saline, LPS (Escherichia coli 0.1 mg/kg), or SEB (1 mg/kg). After 24 h, lung PMN accumulation was determined by myeloperoxidase (MPO) assay and bronchoalveolar lavage fluid cell count (BALfcc). Total lung and BALf MIP-2 was measured by enzyme-linked immunosorbent assay. RESULTS: There was an increase in lung PMN accumulation (by both MPO and BALfcc) and MIP-2 following LPS and SEB in wild-type mice compared to saline-treated controls. In contrast, TLR-4 mice failed to exhibit an increase in lung MIP-2 or PMN accumulation following either LPS or SEB compared to wild-type mice. CONCLUSIONS: TLR-4 mutant mice are unresponsive to intratracheal LPS. SEB elicited an increase in lung MIP-2 and PMN accumulation in wild-type mice. However, TLR-4 mutant mice were protected from this process. This suggests that TLR-4 signaling may mediate the responses to other PAMPs in addition to LPS.

Animals↗
PubMed2002

Cytokines for surgeons.

All cells maintain continuous communication. Hormones derive constitutively from specialized cells to effect total body homeostasis. Conversely, cytokines are produced sporadically from almost all nucleated cells in response to surgical ischemia/septic challenge. Surgical patients are a stew of pulsating cytokines, which serve as the language between all surgically stressed somatic and myeloid cells. Therapeutic manipulation of cytokines has already generated some exhilarating success stories and some crushing disappointments. This introduction to surgically relevant cytokines is presented with the conviction that cytokine-based therapies of surgical patients will (in the future) prove as beneficial to our patients as antibiotics have in the past.

Chemokines↗
PubMed2002

Neutralization of IL-18 attenuates lipopolysaccharide-induced myocardial dysfunction.

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) have been implicated in cardiac dysfunction during endotoxemia. Because IL-18 is a proinflammatory cytokine known to mediate the production of TNF-alpha and IL-1beta and to induce the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), we hypothesized that neutralization of IL-18 would attenuate lipopolysaccharide (LPS)-induced cardiac dysfunction. Mice (C57BL/6) were injected with LPS (0.5 mg/kg ip) or vehicle (normal saline), and left ventricular developed pressure (LVDP) was determined by the Langendorff technique. LVDP was depressed by 38% at 6 h after LPS. LPS-induced myocardial dysfunction was associated with increased myocardial levels of TNF-alpha and IL-1beta as well as increased expression of ICAM-1/VCAM-1. Pretreatment with neutralizing anti-mouse IL-18 antibody attenuated LPS-induced myocardial dysfunction (by 92%) and was associated with reduced myocardial IL-1beta production (65% reduction) and ICAM-1/VCAM-1 expression (50% and 35% reduction, respectively). However, myocardial TNF-alpha levels were not influenced by neutralization of IL-18. In conclusion, neutralization of IL-18 protects against LPS-induced myocardial dysfunction. IL-18 may mediate endotoxemic myocardial dysfunction through induction of and/or synergy with IL-1beta, ICAM-1, and VCAM-1.

Animals↗
PubMed2002

Interleukin-11 attenuates human vascular smooth muscle cell proliferation.

Interleukin (IL)-11 is a growth factor for megakaryocytes, osteoclasts, and intestinal mucosa. IL-11 is also an anti-inflammatory agent, mediating many of its effects by inhibition of the transcriptional activator nuclear factor (NF)-kappa B. The purposes of this study were to examine the effects of IL-11 on human vascular smooth muscle cell (VSMC) proliferation and NF-kappa B activity. VSMC were cultured from human transplant donor aortas, stimulated with basic fibroblastic growth factor (bFGF), and treated with IL-11. VSMC stimulated with bFGF demonstrated an increase in cell number by direct cell counting and mitochondrial activity. IL-11 caused a concentration-dependent decrease in bFGF-induced VSMC proliferation. Furthermore, IL-11 attenuated bFGF-induced increases in cytoplasmic and intranuclear unbound NF-kappa B p65. Similarly, IL-11 attenuated VSMC expression of two NF-kappa B-dependent cytokines, IL-8 and IL-6. Stimulated VSMC did not secrete IL-11, suggesting that endogenous IL-11 did not account for our observations. In conclusion, IL-11 inhibits human VSMC proliferation in vitro and is associated with suppression of NF-kappa B.

Aorta↗
PubMed2002

Lack of TNF-alpha attenuates intimal hyperplasia after mouse carotid artery injury.

This study sought to determine the influence of tumor necrosis factor-alpha (TNF-alpha) on intimal hyperplasia (IH) and characterize the mechanisms of transcriptional regulation after vascular injury. A murine model of wire carotid artery injury was employed to induce IH in wild-type (WT) and TNF-alpha-deficient [TNF(-/-)] animals. Three days after injury, TNF-alpha and nuclear factor-kappaB (NF-kappaB) protein expression was markedly increased in the injured WT carotid artery compared to control. Injury increased TNF-alpha and NF-kappaB mRNA expression 100- and 7.5-fold, respectively. Compared with WT specimens, injury in TNF(-/-) animals decreased both NF-kappaB mRNA and protein nearly 7.5- and 4-fold, respectively. Expression of the NF-kappaB-dependent cytokine monocyte chemotactic protein 1 was markedly diminished in injured TNF(-/-) animals. Finally, TNF(-/-) animals demonstrated a sevenfold reduction in IH compared with WT animals. Cumulatively, these data mechanistically link TNF-alpha and NF-kappaB in vivo and suggest an important influence of TNF-alpha on postinjury IH.

Animals↗
PubMed2002

ICAM-1 and VCAM-1 mediate endotoxemic myocardial dysfunction independent of neutrophil accumulation.

Both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been implicated in neutrophil-mediated lung and liver injury during sepsis. However, the role of these adhesion molecules as well as the contribution of neutrophils in myocardial dysfunction during sepsis remains to be determined. The purpose of this study was to examine the role of ICAM-1, VCAM-1, and neutrophils in lipopolysaccharide (LPS)-induced myocardial dysfunction. Mice were subjected to LPS (0.5 mg/kg ip) or vehicle (normal saline), and left ventricular developed pressure (LVDP) was determined by the Langendorff technique. LVDP was depressed by nearly 40% at 6 h after LPS. Immunofluorescent staining revealed a temporal increase in myocardial ICAM-1/VCAM-1 expression and neutrophils after LPS. Antibody blockade of VCAM-1 reduced myocardial neutrophil accumulation and abrogated LPS-induced cardiac dysfunction. Antibody blockade or absence of ICAM-1 (gene knockout) also abrogated LPS-induced cardiac dysfunction but did not reduce neutrophil accumulation. Neutrophil depletion (vinblastine or antibody) did not protect from LPS-induced myocardial dysfunction. Our results suggest that although endotoxemic myocardial dysfunction requires both ICAM-1 and VCAM-1, it occurs independent of neutrophil accumulation.

Animals↗
PubMed2002

Vasopressin in cardiovascular patients: therapeutic implications.

Vasopressin is a vital homeostatic protein which regulates fluid balance via its antidiuretic effects and vascular tone via its vasoconstrictive effects. Endogenous vasopressin deficiency has been implicated in several disease states resulting in vasodilatory shock. In particular, vasopressin levels are low in patients following cardiac surgery and in those with ventricular dysrhythmias. Several recent studies have demonstrated the effectiveness of exogenous vasopressin in providing haemodynamic support in patients with postcardiopulmonary bypass vasodilatory shock and refractory ventricular fibrillation. This manuscript reviews the pathophysiological and clinical basis for vasopressin replacement in patients with cardiovascular collapse.

Cardiopulmonary Resuscitation↗
PubMedDate not supplied

Ischemic preconditioning: fact or fantasy?

Fifteen years ago, an experimental effort to magnify a myocardial infarction, with preinfarction episodes of transient ischemia, proved paradoxically protective. In the ensuing years, surgeons have learned to discriminate a biochemical/metabolic/functional spectrum of cardiac states ranging from healthy myocardium to "stunned" or "hibernating" heart to the modes of "apoptotic" or "necrotic" cardiomyocyte death. It is now clear that "protective cardiac preconditioning" influences all of these cardiac states. The cellular mechanisms of preconditioning (PC) are now sufficiently understood to permit clinical application. Ligation of adrenergic, adenosine, bradykinin or opioid receptors involves signaling via both tyrosine and calcium-dependent protein kinases (PKC), which activate mitochondrial ATP-dependent potassium channels. Subsequently, the release of oxygen radicals induces nuclear translocation of transcriptional regulators, which transform the cardiomyocyte into a more resilient cell. Although preconditioning was initially recognized as protecting only against infarction, PC also limits postischemic dysrhythmias and enhances contractile function. Phase I (safety) and phase II (efficacy) clinical trials now persuasively support pharmacological preconditioning as a safe mode of preventing postcardiac surgical complications. Indeed, preconditioning is currently being proposed as adjunctive to hypothermic perfusates in protecting against the obligate organ ischemia during transplantation.

Animals↗