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Daniel R Meldrum

Publications and source records attributed to Daniel R Meldrum.

At least 19 recordsLinked to original sources
PubMed2005

Cellular and molecular mechanisms of sex differences in renal ischemia-reperfusion injury.

Renal ischemia-reperfusion (I/R) is an important etiopathological mechanism of acute renal failure (ARF). Despite improvements in the treatment of ARF, it is associated with significant morbidity and mortality. I/R injury also occurs during renal transplantation and leads to reduced allograft survival. Sex differences have been found in I/R injury in many different organs including the kidney. Women have half the mortality of men in ARF. In animal models also, females are protected against renal I/R injury. The mechanisms by which sex affects the outcome to renal I/R injury are being actively investigated. This review will examine the evidence for gender differences in renal I/R injury and discuss the probable mechanisms by which sex affects the renal response to I/R injury.

Acute Kidney Injury↗
PubMed2005

Preconditioning: gender effects.

Preconditioning is injury induced protection from subsequent injury. During preconditioning protective cellular responses to injury are up regulated resulting in acute and delayed defense against further damage. Several studies indicate that females experience a protective advantage after acute insult compared to males. Despite evidence of gender differences in acute injury, relatively few studies have evaluated whether there are sex differences in preconditioning. Variations in patients' pre-morbid preconditioning status may explain outcome variations that are not apparent in small animal studies. This review discusses the differences in response to acute injury experienced by males and females, the basic mechanisms of preconditioning, and the sex differences in the mechanisms of preconditioning.

Animals↗
PubMed2005

Is the preconditioning threshold different in females?

BACKGROUND: Preconditioning is injury induced protection against subsequent insult. Studies have shown that both males and females may be preconditioned. Females appear to have an innate cardioprotection, therefore, we hypothesized that the preconditioning threshold may differ between males and females. MATERIALS AND METHODS: Male and female rats were divided into five groups (n=4-9). Animals were given an intraperitoneal (i.p.) injection of 125, 250, or 500 micrograms/kilogram Salmonella typhimurium lipopolysaccharide (ETX) or 0.4-ml normal saline (NS). After 24-h incubation another i.p. injection of either 500 micrograms/kilogram ETX (injury dose) or NS was given and the animals incubated an additional 6 h. Shams received two injections of NS. Non-preconditioned rats (PC-) received NS followed by ETX. Preconditioned rats had i.p. injections of 125 mug/kg ETX (PC +125), 250 microg/kg ETX (PC +250), or 500 microg/kg ETX (PC +500) followed by the injury dose ETX. The rats were then anesthetized and myocardial function evaluated with the Langendorff perfusion model. RESULTS: PC +500 females were preconditioned and were able to maintain cardiac function similar to shams. Conversely, PC +125 females were not preconditioned with this stimulus and had a significant decrease in cardiac function similar to PC- rats. Male PC +500 and PC +125 rats, however, retained cardiac function comparable to shams, while PC- males showed a significant decrement. CONCLUSIONS: Males and females may each be preconditioned by endotoxin; however, the preconditioning threshold is higher in females than males.

Animals↗
PubMed2005

Intracellular signaling mechanisms of sex hormones in acute myocardial inflammation and injury.

Sex hormones are important modifiers of the acute inflammatory response to injury, an important aspect of myocardial depression and apoptosis following ischemia or endotoxemia. Hemorrhage, trauma, ischemia/reperfusion, burn and sepsis each lead to cardiac dysfunction. Gender has been shown to influence the inflammatory response as well as outcomes following acute injury. The mechanisms by which sex affects the inflammatory response and the outcome to acute injury are being actively investigated. It is now recognized that myocardial inflammation plays a crucial role in I/R-induced myocardial dysfunction. Inflammatory mediators, such as TNF-alpha are produced by cardiomyocytes and contribute to myocardial functional depression and apoptosis. Gender differences in the inflammatory response following burn injury have been demonstrated. However, gender differences in the setting of acute I/R-induced inflammation are unclear. In addition, a critical component of the signal transduction pathway leading to myocardial inflammation is the activation of p38 mitogen-activated protein kinase (MAPK). In other systems, it appears that gender differences exist in the p38 MAPK signaling pathway. The inflammatory response, including the p38 MAPK signaling cascade and expression of proinflammatory cytokines such as TNF-alpha and IL-1beta, may precipitate cardiomyocyte apoptosis following I/R injury. Apoptosis may be an essential component in the pathogenesis of heart failure, and there is evidence that myocyte apoptosis in the failing human heart is markedly lower in women than in men. The prevention of cell death attenuates I/R-induced injury on myocardial anatomy and performance. This review will: 1) examine evidence for gender differences in the outcome to acute injury; 2) explain the myocardial inflammatory response to acute injury; and 3) elucidate the various mechanisms by which gender and sex hormones affect the myocardial response to acute injury.

Acute Disease↗
PubMed2005

Endothelium-dependent pulmonary artery vasorelaxation is dysfunctional in males but not females after acute lung injury.

BACKGROUND: Mortality after acute respiratory distress syndrome is higher in males than in females. Gender differences in pulmonary vascular reactivity and local inflammatory response may explain this disparity. We hypothesized that endothelium-dependent pulmonary vasorelaxation is impaired in males and that this effect is related to differences in local inflammatory cytokine expression from the pulmonary vasculature. METHODS: Pulmonary artery (PA) rings (n = 12-16 per group) were isolated from adult male and female Sprague-Dawley rats treated with endotoxin (Salmonella typhimurium lipopolysaccharide, 20 mg/kg IP) or vehicle (0.9% normal saline), and connected to force transducers for measurement of isometric force displacement. Dose-response curves (0.01-10 micromol/L) to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside were generated. PA rings were also evaluated for inducible nitric oxide synthase, tumor necrosis factor-alpha, and interleukin 1beta messenger RNA (mRNA) by reverse transcriptase-polymerase chain reaction. RESULTS: Endotoxin had no effect on the maximum PA contraction in males (564.4 +/- 37.37 mg vs 633.3 +/- 54.67 mg vehicle) or females (446.3 +/- 20.00 mg vs 444.2 +/- 33.02 mg vehicle), but endothelium-dependent vasodilation was significantly decreased in males (47.49 +/- 5.63% vs 77.61 +/- 9.41% vehicle). Endothelium-independent vasodilation remained intact during endotoxemia. Endotoxin increased the PA expression of inducible nitric oxide synthase mRNA, but there was no gender difference. There was no change in expression of PA tumor necrosis factor, whereas endotoxemic males, but not females, had increased interleukin 1beta mRNA, compared with vehicle. CONCLUSIONS: These results suggest that sepsis-induced vascular dysfunction differs between males and females, and, therefore, treatment of acute lung injury may require gender-specific therapies.

Animals↗
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↗