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Biomedical subjects

Ben M Tsai

Publications and source records attributed to Ben M Tsai.

At least 19 recordsLinked to original sources
PubMed2007

Selective protein kinase C inhibition attenuates pulmonary artery cytokine expression without affecting hypoxic pulmonary vasoconstriction.

Hypoxic pulmonary vasoconstriction may be an adaptive response to shunt blood to well-oxygenated areas of the lung, but hypoxia-induced inflammatory cytokine production leads to acute lung injury. We have previously shown that protein kinase C (PKC) mediates both hypoxic pulmonary vasoconstriction and inflammatory cytokine expression from the pulmonary artery; however, the effect of specific PKC isoform inhibition is currently unknown. We hypothesized that inhibition of classical PKC (cPKC) isoforms would attenuate hypoxic pulmonary vasoconstriction and downregulate hypoxia-induced pulmonary artery cytokine expression. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings (n = 6 per group) during hypoxia (95% N2/5% CO2) in the presence of the nonspecific PKC inhibitor bisindolylmaleimide (1 micromol/L), the cPKC inhibitor Gö 6976 (1 - 10 micromol/L), or vehicle (dimethyl sulfoxide, 0.001%). After 60 min of hypoxia, pulmonary artery rings were analyzed for tumor necrosis factor (TNF) alpha and interleukin (IL) 1beta messenger RNA via reverse transcriptase-polymerase chain reaction. Nonspecific PKC inhibition (bisindolylmaleimide) significantly attenuated hypoxic pulmonary vasoconstriction (44.59 +/- 10.52% vs. 87.06 +/- 10.91% vehicle; P < 0.001) and downregulated hypoxia-induced expression of pulmonary artery TNF-alpha. Specific cPKC inhibition (Gö 6976) attenuated pulmonary artery TNF-alpha expression but had no effect on hypoxic pulmonary vasoconstriction. These data are indicative of the following: (1) nonspecific PKC inhibition attenuates both hypoxic pulmonary vasoconstriction and pulmonary artery TNF-alpha expression, (2) cPKC inhibition downregulates hypoxia-induced pulmonary artery TNF-alpha expression but has no effect on hypoxic pulmonary vasoconstriction, and (3) hypoxic pulmonary vasoconstriction and hypoxia-induced pulmonary artery cytokine expression are independent processes.

Animals↗
PubMed2006

Tumor necrosis factor receptor 1 signaling resistance in the female myocardium during ischemia.

BACKGROUND: Tumor necrosis factor-alpha (TNF) is increased in myocardial tissue after ischemia and reperfusion (I/R). TNF contributes to postischemic myocardial dysfunction and induces proinflammatory signaling, which may be mediated by the 55-kDa TNF receptor (TNFR1). In humans, there is a direct correlation between functional capacity, survival, and circulating TNF levels. Although decreasing the TNF level in animals was beneficial after myocardial ischemia, simply decreasing the bioavailability of TNF in humans with heart failure was not beneficial. This led to the important appreciation that TNF may have beneficial or deleterious effects in the heart, depending on which of its receptors is activated. Females have a lower incidence of heart failure and a higher heart failure survival than males. We hypothesized that TNFR1 signaling resistance occurs in the female myocardium during ischemia. METHODS AND RESULTS: Hearts from male and female TNFR1-knockout and wild-type (WT) mice were subjected to I/R. Female WT mice had better postischemic recovery than did male WT mice, an effect that appeared to be due to TNFR1 signaling resistance in females. Female WT mice had less myocardial depression after TNF infusion despite equivalent TNFR1 expression. Interestingly, TNFR1 ablation improved postischemic myocardial function, decreased activation of p38 mitogen-activated protein kinase, and reduced expression of interleukins-1beta and -6 in males but not in females. Furthermore, WT females expressed more of the suppressor of cytokine signaling protein 3 after I/R, which may in part explain TNFR1 signaling resistance in the female myocardium. CONCLUSIONS: This study demonstrates that sex differences exist in myocardial TNF signaling by TNFR1 after I/R.

Animals↗
PubMed2006

Therapeutic concepts for hypoxic pulmonary vasoconstriction involving ion regulation and the smooth muscle contractile apparatus.

Hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension present a common and formidable clinical problem for practicing intensivists, thoracic, transplant, and trauma surgeons. The Redox Theory for the mechanisms of HPV has provided researchers with a new understanding of the etiology behind HPV that has opened the door to many new avenues of therapy for the disease. Potassium channels have been proposed to be the main mediator contributing to HPV, and treatment concepts that attempt to manipulate the function and number of those channels have been explored. Additionally, attempts to transfer genes that express the formation of specific potassium channels directly into pulmonary hypertensive lungs have proven to be very promising. Finally, rho kinase (ROK) has been discovered to play a very central role in the formation of hypoxia-induced pulmonary hypertension, and the advent of very specific ROK inhibitors has shown positive clinical results. The purposes of this review are to: (1) briefly discuss some of the basic mechanisms that undergird HPV, including the Redox Theory for the mechanisms of HPV; (2) address current research involving treatments concepts related to ion channels; (3) report on research involving gene therapy to combat pulmonary hypertension; and (4) examine potential therapeutic avenues associated with inhibition of rho kinase.

Humans↗
PubMed2006

p38 mitogen-activated protein kinase mediates the sustained phase of hypoxic pulmonary vasoconstriction and plays a role in phase I vasodilation.

Hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension present common and formidable clinical problems for thoracic, transplant, and trauma surgeons. We hypothesized that acute hypoxia causes pulmonary artery (PA) contraction and that p38 mitogen-activated protein (MAP) kinase is a key mediator in that process. To test this hypothesis, we measured isometric force displacement in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the selective p38 MAP kinase inhibitor SB-20358, and stimulator anisomycin. In separate experiments, we measured the functional effects in isolated rat pulmonary artery rings of inhibiting p38 MAP kinase during normoxic conditions. p38 MAP kinase inhibition significantly attenuated the delayed, but not early, contractile phase of HPV. Additionally, stimulation of p38 MAP kinase significantly decreased the phase I vasodilation of HPV. Under normoxia conditions, there was no statistically significant difference in isometric force displacement between control and p38 MAPK inhibitor-treated pulmonary artery rings. We conclude that p38 MAP kinase may be a key mediator in the pathogenesis of HPV and that further understanding may lead to new therapies for HPV associated with acute lung injury.

Animals↗
PubMed2006

17-beta-Estradiol decreases p38 MAPK-mediated myocardial inflammation and dysfunction following acute ischemia.

Understanding the inflammatory response to myocardial ischemia is an important part of achieving the elusive clinical goal of perfect myocardial protection. While it is established that estrogen affects the chronic inflammatory processes of coronary atherosclerosis, the effects of estrogen on acute myocardial proinflammatory signaling are unknown. To study this, myocardial ischemia and reperfusion was performed in rat hearts from normal adult males, normal adult females, ovariectomized (OVX) females, males supplemented with E2, and OVX females supplemented with E2. Following reperfusion, homogenized hearts were analyzed for TNF-alpha, IL-1beta, and IL-6 gene and protein expression, p38 MAPK activation, and the apoptosis-related proteins caspase-3 and Bcl-2. Hearts from proestrus females demonstrated significantly better post-ischemic functional recovery than males. E2 supplementation to males and OVX females improved post-ischemic myocardial functional recovery, reduced the production of TNF-alpha, IL-1beta and IL-6, and decreased the activation of p38 MAPK and caspase-3 when compared to their untreated counterparts. These results suggest that the effect of estrogen on cardioprotection against myocardial I/R may be attributed to its anti-inflammatory and anti-apoptotic properties. Further understanding of these mechanisms may allow therapeutic manipulation of sex hormones in the treatment of acute ischemic injury.

Animals↗
PubMed2006

Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression.

BACKGROUND: Perioperative pulmonary hypertension is a challenging clinical problem with numerous etiologies including hypoxia, adrenergic stimulation, and local inflammation. New oral phosphodiesterase-5 (PDE-5) inhibitors used for the treatment of erectile dysfunction may have beneficial effects on the pulmonary vasculature owing to the abundance of PDE-5 receptors in the lung. The purpose of this study was to compare the efficacy of sildenafil, vardenafil, and tadalafil in preventing acute hypoxic pulmonary vasoconstriction and hypoxia-induced pulmonary artery tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1beta) expression. METHODS: Isolated rat pulmonary arteries suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), sildenafil, vardenafil, or tadalafil to assess (1) pulmonary artery relaxation; (2) inhibition of phenylephrine-induced pulmonary artery contraction; (3) inhibition of hypoxic pulmonary vasoconstriction (pO2 = 30-35 mm Hg); and (4) hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression (reverse transcriptase-polymerase chain reaction). RESULTS: Sildenafil, vardenafil, and tadalafil resulted in dose-dependent pulmonary artery relaxation and inhibited phenylephrine-induced pulmonary artery contraction, but only tadalafil significantly inhibited hypoxic pulmonary vasoconstriction (52.08% +/- 7.65% tadalafil versus 88.63% +/- 8.96% vehicle; 98.61% +/- 10.04% sildenafil; 68.46% +/- 15.84% vardenafil). Hypoxia-induced upregulation of TNF-alpha and IL-1beta mRNA in pulmonary artery was significantly decreased by tadalafil, but not sildenafil or vardenafil pretreatment. CONCLUSIONS: We conclude that sildenafil, vardenafil, and tadalafil were equally efficacious in causing pulmonary artery relaxation, but only tadalafil inhibited hypoxic pulmonary vasoconstriction and attenuated hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Disparate IL-1beta and iNOS gene expression in the aorta and pulmonary artery after endotoxemia.

BACKGROUND: Endotoxemia causes paradoxical effects on the systemic and pulmonary vasculature, resulting in systemic hypotension and increased pulmonary artery pressure. The local production of inflammatory mediators may have important effects on vascular tissue function. The purpose of this study was to delineate differences in function and the expression of tissue cytokine genes in the aorta and pulmonary artery after endotoxemia. METHODS: Thoracic aorta and pulmonary artery branches were isolated from adult Sprague- Dawley rats (n = 4-6/group) 6 h after intraperitoneal injection of lipopolysaccharide (Salmonella typhimurium, 20 mg/kg) or vehicle (1.0 mL of saline). Arteries were suspended in perfused organ baths for measurement of isometric force transduction, and dose-response curves to phenylephrine (0.01-10 micromol/L), acetylcholine (0.01-10 micromol/L), and sodium nitroprusside (0.001-10 micromol/L) were generated. The vascular segments were also assessed for expression of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) by semiquantitative reverse transcriptase- polymerase chain reaction. RESULTS: Endotoxemia resulted in decreased contractility of the aorta (508.63 +/- 81.89 mg vs. 2544.16 +/- 142.05 mg in the vehicle group) and pulmonary artery (352.50 +/- 38.11 mg vs. 535.83 +/- 45.51 mg in the vehicle group) and decreased endothelium-dependent pulmonary artery relaxation (52.86 +/- 5.63% vs. 80.58 +/- 6.39% in the vehicle group). Expression of IL-1beta and iNOS mRNA by the pulmonary artery, but not the aorta, increased significantly in the endotoxintreated animals. Interleukin-6 was increased in both the pulmonary artery and the aorta during endotoxemia, whereas TNF concentrations were unchanged. CONCLUSIONS: Endotoxemia may cause aortic hypocontractility and impaired endothelium-dependent pulmonary artery vasorelaxation. Expression of inflammatory genes in vascular tissue may be site-specific and may contribute to the functional derangements associated with sepsis.

Animals↗
PubMed2006

Experimental therapies for hypoxia-induced pulmonary hypertension during acute lung injury.

Hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension present a common and formidable clinical problem for practicing thoracic, transplant, and trauma surgeons. The recent discovery of efficacious drugs that are selective for the pulmonary vasculature has brought about the potential for very powerful therapeutic agents. Inhaled nitric oxide (NO) therapy has already found broad clinical utility, yet its use is limited by potential toxicities. Rho kinase (ROK) has been discovered to play a very central role in the formation of hypoxia induced pulmonary hypertension, and the advent of very specific ROK inhibitors has shown positive clinical results. Finally, phosphodiesterase-5 inhibitors have been found to selectively vasodilate the pulmonary vasculature in the midst of HPV. The purposes of this review are to: 1) discuss the advantages and disadvantages of inhaled preparations of NO; 2) address experimental alternatives to inhaled preparations of NO to treat HPV; 3) explore potential therapeutic avenues associated with inhibition of Rho-kinase; and, 4) examine the use of phosphodiesterase-5 (PDE-5) inhibitors and combination therapy in the treatment of HPV.

Animals↗
PubMed2006

Cytokines in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating intra-abdominal emergency in the newborn period. The disease involves bowel wall inflammation, ischemic necrosis, eventual perforation, and the need for urgent surgical intervention. Unrecognized or left untreated, the neonate can decompensate quickly, often progressing to shock, multisystem organ failure, and eventual death. During the past several years, a number of basic science and clinical trials have been established in an attempt to understand the pathophysiology of NEC. As many researchers feel that NEC develops as an uncontrolled inflammatory response that leads to intestinal ischemia, a large number of studies have been focused on the inflammatory cascade and the role that cytokines play within that cascade. Although a large amount of data has been generated from these studies, the events leading to the ischemic injury of the intestine are still not fully understood. This article will therefore focus on the key cytokines involved with NEC, in an attempt to present the current literature and studies that support their involvement.

Cytokines↗
PubMed2006

Pretreatment with adult progenitor cells improves recovery and decreases native myocardial proinflammatory signaling after ischemia.

Cardiogenic shock from myocardial ischemia is the leading cause of death of both men and women. Although adult progenitor cells have emerged as a potential therapy for heart disease, reports indicate that transplanted adult progenitor cells may not differentiate into heart muscle. We hypothesized that pretreatment with adult progenitor cells may protect myocardium from acute ischemic damage. Treatment immediately before an ischemic event removes the possibility that differentiation to heart muscle may account for the observed effects. In the present study, we determined that adult progenitor cells from three different sources (human bone marrow, rat bone marrow, and human adipose tissue) immediately protect native myocardium against ischemia and decrease myocardial proinflammatory and proapoptotic signaling. Postischemic recovery of adult progenitor cell-pretreated hearts was significantly better than that of control hearts. This was correlated with a 50% decrease in proinflammatory cytokine production. The use of a differentiated cell control had no such effect. Therefore, adult progenitor cell pretreatment improved postischemic myocardial function, decreased myocardial production of inflammatory mediators, and limited proapoptotic signaling. These results represent the first demonstration that pretreatment with progenitor cells is myocardial protective. These findings may not only have mechanistic implications regarding the benefit of progenitor cells but may also have clinical therapeutic implications before planned ischemic events.

Animals↗
PubMed2005

Does endogenous testosterone mediate the lower preconditioning threshold in males?

BACKGROUND: Preconditioning is injury-induced protection from subsequent insult. Recent data indicates that males have lower preconditioning thresholds compared to females. Therefore, we hypothesized that testosterone may mediate the lower preconditioning threshold observed in males. MATERIALS AND METHODS: Adult normal and castrated male Sprague-Dawley rats (n = 4-5) were given intraperitoneal (i.p.) injections of 125 or 500 microg/kg Salmonella typhimurium lipopolysaccharide (ETX) or 0.4 ml normal saline (NS). Another i.p. injection of 500 microg/kg ETX (injury dose) was given 24 h later. After 6 h, myocardial function was evaluated via the Langendorff perfusion model. Shams received only NS, while non-preconditioned rats (PC-) received NS followed by the 500 microg/kg ETX injury dose. Preconditioned rats received injections of 125 mug/kg ETX (PC +125) or 500 microg/kg ETX (PC +500), followed by the 500 microg/kg ETX injury dose. RESULTS: Normal PC +125 and PC +500 males were preconditioned and maintained cardiac function similar to shams (P > 0.05). Castrated PC +125 and PC +500 males were also preconditioned and maintained cardiac function similar to castrated shams (P > 0.05). Conversely, both normal and castrated PC-males showed significantly decreased cardiac function compared to shams (P < 0.05). CONCLUSIONS: Endogenous testosterone does not mediate the lower preconditioning threshold in males.

Animals↗
PubMed2005

Endogenous estrogen mediates a higher threshold for endotoxin-induced myocardial protection in females.

Myocardial endotoxin tolerance may be induced in both males and females; however, it remains unknown whether there are mechanistic and threshold differences between the sexes. We hypothesized that endogenous estrogen mediates a higher threshold for endotoxin (ETX)-induced protection in females. Adult proestrus and ovariectomized (OVX) female rats were preconditioned (PC) with intraperitoneal injections of 125 (PC+125) or 500 (PC+500) microg/kg Salmonella typhimurium LPS (ETX) or normal saline (PC-). Twenty-four hours later, injury dose ETX (500 microg/kg) was injected. After 6 h, myocardial function was measured via Langendorff. p38 MAPK and JNK activation and TNF-alpha, IL-1, and IL-6 expression were evaluated. ETX injury significantly decreased left ventricular developed pressure in PC- groups vs. controls. PC+500 regimen protected against ETX injury, resulting in normal cardiac function. PC+125 regimen protected OVX but not proestrus females, which had diminished myocardial function. Activated JNK and TNF-alpha increased in PC- but were diminished in PC+500 animals. Importantly, activated JNK and TNF increased in PC+125 proestrus females, whereas PC+125 OVX females displayed decreases in these molecules. There were no differences in p38 MAPK activation or expression of IL-1 or IL-6. These results demonstrate that proestrus females require a higher stimulus (PC+500) to achieve myocardial protection against ETX injury. Removal of endogenous estrogen (OVX) lowered the preconditioning threshold (PC+125), resulting in protection after lesser injury. Additionally, myocardial JNK and TNF expression was decreased in OVX PC+125 females, which correlated with myocardial function differences. Therefore, we conclude that endogenous estrogen mediates a higher threshold for ETX tolerance in female myocardium.

Animals↗
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

Stem cell transplantation as a therapeutic approach to organ failure.

BACKGROUND: Stem cell transplantation is one of the next great frontiers for surgery. Stem cells, which are undifferentiated and self-renewing, have shown the ability to differentiate into cardiomyocytes, as well as many other cell types for potential therapeutic use by surgeons. MATERIALS AND METHODS: As a result, stem cells have the potential to undo irreversible cellular damage, something traditional therapies could not cure. However, numerous issues must be resolved to permit safe and effective clinical application of stem cell therapy. These include the interpretation of cellular labeling, the origin of replicating myocytes, the homing mechanism of stem cells, and the differentiation process. RESULTS: Successful translational research will depend on precise delivery of these cells in real time to the area of interest, e.g., the spinal cord, liver, or heart. Surgeons will be better able to excise and replace/regrow, rather than excise alone. As such, a basic understanding of stem cell biology will benefit the surgeon scientist and clinical surgeon. CONCLUSIONS: The review: 1) discusses myocardial regeneration; 2) defines and categorizes stem cells; 3) presents evidence of stem cell transdifferentiation into cardiomyocytes; and, 4) delineates the therapeutic potential of stem cells in the treatment of ischemic heart disease.

Cardiomyopathies↗
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↗