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Daniel R Meldrum

Publications and source records attributed to Daniel R Meldrum.

17 recordsLinked to original sources
PubMed2005

Sex differences in the myocardial inflammatory response to acute injury.

Hemorrhage, trauma, ischemia/reperfusion, burn, and sepsis each lead to cardiac dysfunction. These insults lead to an inflammatory cascade, which plays an important role in this process. Gender has been shown to influence the inflammatory response, as well as outcomes after acute injury. The mechanisms by which gender affects the inflammatory response to and the outcome of acute injury are being actively investigated. We searched PubMed for articles in the English language by using the search words sex, gender, estrogen, testosterone, inflammation, acute injury, ischemia reperfusion, sepsis, trauma, and burns. These were used in various combinations. We read the abstracts of the relevant titles to confirm their relevance, and the full articles were then extracted. References from extracted articles were checked for any additional relevant articles. This review will examine evidence for gender differences in the outcome to acute injury, explain the myocardial inflammatory response to acute injury, and elucidate the various mechanisms by which gender affects the myocardial response to acute injury.

Adenosine Triphosphate↗
PubMed2004

Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion.

Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function (left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF-alpha, IL-1beta, and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF-alpha, IL-1beta, and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor (flutamide) or depleting testosterone (castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R.

Acute Disease↗
PubMed2004

Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury.

The myocardium generates inflammatory mediators during ischemia-reperfusion (I/R), and these mediators contribute to cardiac functional depression and apoptosis. The great majority of these data have been derived from male animals and humans. Sex has a profound effect over many inflammatory responses; however, it is unknown whether sex affects the cardiac inflammatory response to acute myocardial I/R. We hypothesized the existence of inherent sex differences in myocardial function, expression of inflammatory cytokines, and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway after I/R. Isolated rat hearts from age-matched adult males and females were perfused (Langendorff), and myocardial contractile function was continuously recorded. After I/R, myocardium was assessed for expression of TNF-alpha, IL-1beta, and IL-6 (RT-PCR, ELISA); IL-1alpha and IL-10 mRNA (RT-PCR); and activation of p38 MAPK (Western blot). All indexes of postischemic myocardial function [left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal positive (+dP/dt) and negative (-dP/dt) values of the first derivative of pressure] were significantly improved in females compared with males. Compared with males, females had decreased myocardial TNF-alpha, IL-1beta, and IL-6 (mRNA, protein) and decreased activation of p38 MAPK pathway. These data demonstrate that hearts from age-matched adult females are relatively protected against I/R injury, possibly due to a diminished inflammatory response.

Animals↗
PubMed2004

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C.

Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. Concomitant production of proinflammatory mediators during hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the PKC inhibitors calphostin C or chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator thymeleatoxin for 60 min. After hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to mRNA analysis for TNF-alpha and IL-1beta via RT-PCR. Our results showed that, in isolated pulmonary arteries, hypoxia caused a biphasic contraction and increased expression of TNF-alpha and IL-1beta mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-alpha and IL-1beta mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application.

Alkaloids↗
PubMed2004

Inflammatory mediators and growth factors in obstructive renal injury.

Obstruction of the upper urinary tract poses a significant clinical challenge to the urologist, and the cascade of renal cellular and molecular events triggered by upper urinary tract obstruction result in a progressive, and eventually permanent, loss in renal function. These pathological changes include the development of renal fibrosis, tubular atrophy, interstitial inflammation, and apoptotic renal cell death. A myriad of cytokines and growth factors have been identified as major contributors to obstruction-induced renal fibrosis and apoptotic cell death, including transforming growth factor-beta1, angiotensin II, nuclear factor-kappaB, and tumor necrosis factor-alpha. This review examines the role of these mediators in obstruction-induced renal injury.

Animals↗
PubMed2004

Endothelial monocyte-activating polypeptide II causes NOS-dependent pulmonary artery vasodilation: a novel effect for a proinflammatory cytokine.

Endothelial monocyte-activating polypeptide (EMAP) II is a novel proinflammatory cytokine that is released from apoptotic and hypoxic cells. The purpose of this study was to determine the effect of EMAP II on the pulmonary artery (PA) and to characterize its mechanism of action. To study this, isolated PA rings from adult male Sprague-Dawley rats were suspended on steel hooks connected to force transducers and immersed in 37 degrees C organ baths containing modified Krebs-Henseleit solution. After equilibration, force displacement of phenylephrine-preconstricted PA was measured in response to EMAP II. Experiments were performed in endothelium-intact rings, endothelium-denuded rings, and in the presence of the NOS inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME). Pulmonary artery rings were then subjected to quantitative PCR analysis for inducible NOS (iNOS) mRNA. EMAP II caused a maximal vasodilation of 251 +/- 30.7 mg in endothelium-intact PA. EMAP II caused no vasodilation in endothelium-denuded and l-NAME-treated PA (20 +/- 14.0 mg and 17.5 +/- 7.5 mg, respectively, P < 0.001 vs. endothelium intact). In addition to its vasoactive properties, EMAP II increased PA iNOS mRNA twofold compared with controls. These results demonstrate that 1) EMAP II causes PA vasodilation; 2) EMAP II-mediated PA vasodilation is endothelium dependent and NOS dependent; and 3) EMAP II upregulates iNOS mRNA expression in PA. This report constitutes the first demonstration of EMAP II's effects on the pulmonary artery, its mechanism of action, and represents the identification of the first proinflammatory cytokine to cause PA vasodilation.

Animals↗
PubMed2004

Hypoxic pulmonary vasoconstriction in cardiothoracic surgery: basic mechanisms to potential therapies.

Hypoxic pulmonary vasoconstriction is postulated to be an adaptive mechanism to match lung perfusion with ventilation; however, the consequences of the maladaptive effects of pulmonary vasoconstriction represent formidable therapeutic challenges. Understanding the basic mechanisms of hypoxic pulmonary vasoconstriction will enhance the assimilation of translational research into clinical practice. The purposes of this review are to (1) define basic mechanisms of pulmonary vasoconstriction and vasorelaxation; (2) delineate the biphasic contractile response to hypoxia; (3) critically examine data that support the mediator hypothesis versus the ion channel hypothesis; and (4) explore potential mechanistic-based therapies for hypoxic pulmonary vasoconstriction.

Adaptation, Physiological↗
PubMed2004

Preconditioning up-regulates the soluble TNF receptor I response to endotoxin.

BACKGROUND: Sepsis and endotoxemia frequently complicate the care of surgical patients. Basic and clinical investigations have correlated tumor necrosis factor alpha (TNF) levels with myocardial suppression and lethality after sepsis. Soluble TNF receptor 1 (sTNFRI) is an endogenous mechanism of clearing serum TNF. Elucidating mechanisms of endogenous adaptation may allow the development of novel therapeutic strategies. Endotoxin tolerance (LPS-preconditioning) is associated with a down-regulation of proinflammatory monokine production; thus, similar down-regulation of sTNFRI may be expected. However, it may be equally plausible to hypothesize that the processes which lead to enhanced shedding of these receptors are up-regulated during tolerance. MATERIALS AND METHODS: To study this, sublethal LPS was administered to male rats (Salmonella typhimurium, 500 microg/kg IP in 1 ml bacteriostatic normal saline IP) or an equivalent volume of bacteriostatic normal saline IP (sham) 24 h prior to subsequent LPS challenge. Rats were sacrificed at 0, 1, 2, 4, 6, and 24 h following LPS and serum TNF and TNFRI were measured by ELISAs. RESULTS: LPS induced a significant increase in sTNFRI at 1, 2, 4, and 6 h following LPS. sTNFRI levels returned to baseline by 24 h following LPS treatment. LPS induced a parallel increase in TNF. LPS pretreatment (preconditioning) resulted in a significant increase in TNFRI and a significant decrease in TNF. CONCLUSION: This study constitutes the initial demonstration that tolerance mechanisms: (1) up-regulate sTNFRI, which binds and clears TNF; and (2) reverses the TNF-to-sTNFRI ratio. Safe pharmacologic methods of up-regulating endogenous TNF-clearance mechanisms may ultimately have therapeutic value.

Animals↗
PubMed2004

Unilateral ureteral obstruction induces renal tubular cell production of tumor necrosis factor-alpha independent of inflammatory cell infiltration.

PURPOSE: Obstructive uropathy is a significant clinical problem that results in apoptotic renal cell death and progressive renal fibrosis. A number of different inflammatory mediators have been implicated in the pathophysiology of obstruction induced renal injury including tumor necrosis factor-alpha (TNF)-alpha. The cellular source of obstruction induced renal TNF-alpha production and its relationship to renal inflammatory cell infiltration remain unknown. MATERIALS AND METHODS: Male Sprague-Dawley rats were anesthetized and exposed to varying lengths of unilateral ureteral obstruction vs sham operation. The kidneys were harvested following renal injury and evaluated for TNF-alpha mRNA expression (reverse transcriptase polymerase chain reaction), TNF-alpha protein production (enzyme-linked immunosorbent assay), TNF-alpha cellular localization (immunohistochemistry) and leukocyte infiltration (leukocyte staining). RESULTS: Renal TNF-alpha mRNA expression and protein production peaked following 3 days of ureteral obstruction (54 +/- 5% vs sham 22 +/- 9% of glyceraldehyde-3-phosphate dehydrogenase mRNA, p <0.05 and 204 +/- 13 vs sham 84 +/- 9 pg/ml, p <0.05, respectively). TNF-alpha production localized primarily to renal cortical tubular cells following obstruction and the time point of maximal TNF-alpha production (3 days of obstruction) were not associated with a significant renal inflammatory cell infiltrate. CONCLUSIONS: TNF-alpha is produced by the renal cortical tubular cells in response to ureteral obstruction and independent of a significant inflammatory cell infiltrate. Identification of the cellular source of TNF-alpha expression during renal obstruction may have therapeutic implications for the targeted inhibition of TNF-alpha production and potential amelioration of obstructive renal injury.

Animals↗
PubMed2004

P38 MAPK mediates myocardial proinflammatory cytokine production and endotoxin-induced contractile suppression.

Cardiac myocytes are capable of synthesizing tumor necrosis factor alpha (TNF-alpha), interleukin-1, and interleukin-6 (IL-1 and IL-6). p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant-stress-induced myocardial TNF-alpha production; however, the extent to which this kinase contributes to endotoxin-induced contractile dysfunction, as well as TNF-alpha, IL-1alpha, IL-1beta, and IL-6 production, in a bloodless model of endotoxin-induced myocardial dysfunction is unknown. Isolated rat hearts were perfused (Langendorff), and myocardial contractile function continuously recorded, during direct antegrade endotoxin infusion, with and without prior p38 MAPK inhibition. Ventricular p38 MAPK activation (phospho-p38 MAPK Western), cytokine mRNA (RT-PCR), and protein (ELISA) were determined. Endotoxin resulted in progressive decline in left ventricular developed pressure and coronary flow that was attenuated with prior p38 MAPK inhibition (SB 203580). p38 MAPK inhibition significantly decreased endotoxin-induced cardiac TNF-alpha, IL-1alpha, IL-1beta, and IL-6 mRNA levels. To determine the relative effect of TNF-alpha in inducing IL-1alpha, IL-1beta, and IL-6 production, TNF-alpha was sequestered during endotoxin infusion, and TNF-alpha, IL-1beta, and IL-6 protein levels were measured. Interestingly, TNF-alpha sequestration alone significantly decreased myocardial IL-1beta and IL-6 production. We conclude that p38 MAPK is involved in endotoxin-induced myocardial contractile dysfunction and myocardial TNF-alpha production; however, p38 MAPK's involvement in IL-1 and IL-6 production may be indirectly mediated by TNF-alpha.

Animals↗
PubMed2004

Preconditioning: evolution of basic mechanisms to potential therapeutic strategies.

Preconditioning describes the phenomenon by which a traumatic or stressful stimulus confers protection against subsequent injury. Originally recognized in dog heart subjected to ischemic challenges, preconditioning has been demonstrated in multiple species, can be induced by various stimuli, and is applicable in different organ systems. Tremendous progress has been made elucidating the signal transduction cascade of preconditioning. Preconditioning represents a potent tissue-protective condition, and mechanistic understanding may allow safe clinical application. This review recalls the history of preconditioning and how it relates to the history of the investigation of endogenous adaptation; summarizes the current mechanistic understanding of acute preconditioning; outlines the signal transduction cascade leading to the development of delayed preconditioning; discusses preconditioning in noncardiac tissue; and explores the potential of using preconditioning clinically.

Animals↗
PubMed2003

Insulin-like growth factor-1 in myocardial tissue: interaction with tumor necrosis factor.

Insulin-like growth factor (IGF)-1 is a well characterized growth factor that plays a role in the regulation of myocardial structure and function. Using an ex vivo murine model, Davani and coworkers, in this issue of Critical Care, demonstrate that IGF-1 confers cardiac protection against ischemia via mitochondria-dependent mechanisms. Those investigators used the ratio of mitochondrial to nuclear DNA to demonstrate that IGF-1, which prevents reduction in this ratio during reperfusion, provides cytoprotection. This commentary also reviews mechanisms of IGF-1 function and provides a graphic representation of IGF-1 signaling mechanisms in potential crosstalk relations with mediators of inflammation in the heart (specifically tumor necrosis factor-alpha).

Animals↗
PubMed2003

On-pump coronary artery bypass surgery activates human myocardial NF-kappaB and increases TNF-alpha in the heart.

PURPOSE: Myocardial tumor necrosis factor alpha (TNF) production and nuclear factor kappa B (NF-kappaB) activation has been demonstrated in chronic heart failure and experimental models of acute ischemia-reperfusion injury. Further, a cause and effect relationship has been established between these events and cardiomyocyte apoptosis following such conditions. It remains unknown, however, whether the myocardial injury associated with coronary artery bypass surgery (CAB) results in myocardial NF-kappaB activation and TNF production. We hypothesized that CAB with cardiopulmonary bypass ("on-pump") activates human myocardial NF-kappaB and increases TNF in the heart. METHODS: Patients, 18 to 65 years of age, scheduled for elective cardiac surgery but without other preexisting disease were considered eligible for the study. Biopsies of human myocardium were obtained before and after cardiopulmonary bypass and myocardial TNF levels were determined by ELISA and cytotoxicity assay, and NF-kappaB activation was determined by electrophoretic mobility shift assay (n = 6 patients). NF-kappaB activation was quantitated with gel densitometry. RESULTS: The clinical characteristics of the study patients were as follows (means +/- SEM): mean age (y) 50.0 +/- 5.7, male 6 (100%), cardiopulmonary bypass time (min) 107 +/- 37.7, cross-clamp time (min) 68 +/- 17.6, number of CAB 3.0 +/- 1.1, and length of hospital stay (d) 4.8 +/- 0.9. Before CAB, myocardial TNF-alpha levels were 251 +/- 22 pg/g and 33 +/- 9 U/g, as determined by ELISA and cytotoxicity assay, respectively. Following CAB, human myocardial TNF-alpha levels increased to 892 +/- 71 pg/g (P = 0.0008) and 141 +/- 11 U/g (P = 0.0042), as determined by ELISA and cytotoxicity assay, respectively. Before CAB, the ratio of bound to unbound NF-kappaB DNA was 0.009 +/- 0.0007 and after CAB the ratio was 0.24 +/- 0.01 (P < 0.0001). CONCLUSIONS: This study represents the initial demonstration that coronary artery bypass grafting results in an activation of NF-kappaB and an increase of TNF in the heart.

Cardiopulmonary Bypass↗
PubMed2003

Liposomal delivery of heat shock protein 72 into renal tubular cells blocks nuclear factor-kappaB activation, tumor necrosis factor-alpha production, and subsequent ischemia-induced apoptosis.

Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of cells from toxins, thermal stress, and ischemic injury. The cytoprotective role and mechanism of action of HSP72 in renal cell ischemic injury remain unclear. To study this, HSP72 was introduced (liposomal transfer) or induced (thermal stress, 43 degrees Cx1 hour) in renal tubular cells (LLC-PK1) with Western blot confirmation. Cells were subjected to simulated ischemia 24 hours after liposomal HSP72 transfer or thermal stress, and the effect of HSP72 on nuclear factor-kappaB (NF-kappaB) activation (electrophoretic mobility shift assay and immunohistochemistry), IkappaBalpha production (Western blot), postischemic tumor necrosis factor-alpha (TNF-alpha) production (RT-PCR), and apoptosis (TUNEL assay) were determined. In separate experiments, the role of TNF-alpha in apoptosis was determined (anti-TNF-alpha neutralizing antibody). Results demonstrated that both liposomal transfer of HSP72 and thermal induction of HSP72 prevented NF-kappaB activation and translocation, TNF-alpha gene transcription, and subsequent ischemia-induced renal tubular cell apoptosis. Furthermore, TNF-alpha neutralization also inhibited ischemia-induced renal tubular cell apoptosis. These results indicate that liposomal delivery of HSP72 inhibits ischemia-induced renal tubular cell apoptosis by preventing NF-kappaB activation and subsequent TNF-alpha production. Further elucidation of the mechanisms of HSP-induced cytoprotection may result in therapeutic strategies that limit or prevent ischemia-induced renal damage.

Animals↗
PubMed2003

The role of estrogen in cardiovascular disease.

Cardiovascular disease is the number one cause of death among women, accounting for nearly 50% of female deaths. Statistics show that women on average develop cardiovascular disease 10 to 15 years later in life than men, and that the risk may increase after menopause. This observation has led to much speculation as to what physiological change(s) associated with menopause is responsible for the higher risk of atherosclerosis. Estrogen, with its potential as a cardioprotective agent and as an immunomodulator of the inflammatory response in atherosclerosis, has received the most attention. Understanding the mechanisms that lead to these differences may allow beneficial therapeutic intervention to enhance this effect in females and evoke this protection in males. This review will do the following: (1) characterize mechanisms of atherosclerosis, (2) explore the role of estrogen-replacement therapy, (3) define the effect of gender on inflammation, (4) compare and contrast the effects of estrogen and testosterone on endothelial functional, and (5) suggest mechanistic based therapeutic opportunities.

Animals↗
PubMed2002

TNF-alpha-dependent bilateral renal injury is induced by unilateral renal ischemia-reperfusion.

While tumor necrosis factor (TNF)-alpha is an important mediator of renal ischemia-reperfusion (I/R) injury, its role in contralateral renal injury after isolated renal ischemia remains unknown. We therefore investigated the effect of isolated left renal ischemia on the nonischemic contralateral kidney. To study this, male Sprague-Dawley rats were anesthetized and exposed to varying degrees of left renal I/R injury. Both kidneys were subsequently harvested, serum samples were obtained, and TNF-alpha protein expression (ELISA), TNF-alpha mRNA content (RT-PCR), TNF-alpha immunolocalization, and neutrophil infiltration (myeloperoxidase assay) were determined. The effect of TNF-alpha on neutrophil infiltration was assessed by neutralizing TNF-alpha with TNF binding protein (TNF-BP) before left renal I/R injury. TNF-alpha protein expression, TNF-alpha mRNA induction, and neutrophil infiltration increased significantly in both kidneys after unilateral renal I/R injury. Furthermore, the administration of TNF-BP before unilateral renal I/R substantially reduced the degree of neutrophil infiltration bilaterally. These results constitute the initial demonstration that unilateral renal I/R induces bilateral TNF-alpha production and neutrophil infiltration through a TNF-alpha-dependent mechanism.

Animals↗