Single-port laparoscopic right hemicolectomy: the first 100 resections.

BACKGROUND: Single-port laparoscopy remains a novel technique in the field of colorectal surgery. Several small series have examined its safety for colon resection. OBJECTIVE: Our aim was to analyze our entire experience and short-term outcomes with single-port laparoscopic right hemicolectomy since its introduction at our institution. We assert that this approach is feasible and safe for the wide array of patients and indications encountered by a colorectal surgeon. DESIGN: This is a retrospective analysis of prospectively gathered data for all patients who underwent single-port laparoscopic right hemicolectomy with the use of standard laparoscopic instrumentation, for malignant or benign disease, between July 2009 and November 2010 in a high-volume, academic, colorectal surgery practice. MAIN OUTCOME MEASURES: Demographic, clinical, operative, and pathologic factors were reviewed and analyzed. All conversions to conventional laparoscopic or open operations were considered in this analysis. RESULTS: One hundred patients underwent single-port laparoscopic right hemicolectomy during the study period. Mean age was 63 years, and 61% of the patients were men. Forty-three percent had undergone previous abdominal surgery, and the median body mass index was 26 (range, 18-46). Median ASA classification was 3 (range, 1-4). Five percent of the operations were performed urgently, and 56% were performed for carcinoma, of which half were T3 or T4 tumor stage. Median operative duration was 105 (range, 64-270) minutes. Mean and median blood loss was 106 and 50 mL. Two percent required conversion to multiport laparoscopy, and 4% converted to the open approach. Median postoperative stay was 4 (range, 2-48) days. Median lymph node number was 18 (range, 11-42). There was one mortality in this series. Morbidity, including wound infection, was 13%. CONCLUSIONS: This represents the largest experience with single-port laparoscopic right hemicolectomy to date. This technique was used with acceptable morbidity and mortality and without compromise of conventional oncologic parameters by colorectal surgeons experienced in minimally invasive technique. These findings support the use of a single-port approach for patients requiring right hemicolectomy.

Localizing ureteral catheters for left-sided colectomy and proctectomy: Do the risks justify the benefits?

BACKGROUND: The role of ureteral catheters in left-sided colectomies and proctectomies remains debated. Given the rarity of ureteral injury, prior retrospective studies were underpowered to detect potentially small, but meaningful differences. This study seeks to determine the role and morbidity of ureteral catheters in left-sided colectomy and proctectomy using a large, national database. METHODS: The National Surgical Quality Improvement Project from 2012 to 2018 was queried. Left-sided colectomies or proctectomies were included. Propensity score matching and multivariable logistic regression analysis was performed. RESULTS: 8419 patients with ureteral catherization and 128,021 patients without catheterization were included. After matching, there was not a significant difference in ureteral injury between the groups (0.7% with vs 0.9% without, p = 0.07). Ureteral catheters were associated with increased overall morbidity and longer operative time. Increasing body mass index, operations for diverticular disease, conversion to open, T4 disease and increasing operative complexity were associated with ureteral injury (p < 0.01 for all). CONCLUSIONS: Ureteral catheterization was not associated with decreased rates of ureteral injury when including all left-sided colectomies. High-risk patients for ureteral injury include those with obesity, diverticular disease, and conversion to open. Selective ureteral catheterization may be warranted in these settings.

Transanal endoscopic microsurgery resection of rectal tumors: outcomes and recommendations.

PURPOSE: Transanal endoscopic microsurgery provides a minimally invasive alternative to radical surgery for excision of benign and malignant rectal tumors. The purpose of this study was to review our experience with transanal endoscopic microsurgery to clarify its role in the treatment of different types of rectal pathology. METHODS: A prospective database documented all patients undergoing transanal endoscopic microsurgery from October 1996 through June 2008. We analyzed patient and operative factors, complications, and tumor recurrence. For recurrence analysis, we excluded patients with fewer than 6 months of follow-up, previous excisions, known metastases at initial presentation, and those who underwent immediate radical resection following transanal endoscopic microsurgery. RESULTS: Two hundred sixty-nine patients underwent transanal endoscopic microsurgery for benign (n = 158) and malignant (n = 111) tumors. Procedure-related complications (21%) included urinary retention (10.8%), fecal incontinence (4.1%), fever (3.8%), suture line dehiscence (1.5%), and bleeding (1.5%). Local recurrence rates for 121 benign and 83 malignant tumors were 5% for adenomas, 9.8% for T1 adenocarcinoma, 23.5% for T2 adenocarcinoma, 100% for T3 adenocarcinoma, and 0% for carcinoid tumors. All 6 (100%) recurrent adenomas were retreated with endoscopic techniques, and 8 of 17 (47%) recurrent adenocarcinomas underwent salvage procedures with curative intent. CONCLUSIONS: Transanal endoscopic microsurgery is a safe and effective method for excision of benign and malignant rectal tumors. Transanal endoscopic microsurgery can be offered for (1) curative resection of benign tumors, carcinoid tumors, and select T1 adenocarcinomas, (2) histopathologic staging in indeterminate cases, and (3) palliative resection in patients medically unfit or unwilling to undergo radical resection.

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.

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.

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.

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.

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.

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.

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.

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.

Zaprinast attenuates hypoxic pulmonary artery injury and causes less aortic relaxation than milrinone.

Hypoxic pulmonary vasoconstriction is a challenging clinical problem with limited therapeutic options. Milrinone, a phosphodiesterase (PDE)-3 inhibitor, is frequently used to treat perioperative pulmonary hypertension. However, recent evidence suggests that the PDE-5 isoform may be more specific for lung tissue. We hypothesized that the PDE-5 inhibitor zaprinast has greater efficacy for pulmonary vasorelaxation, attenuation of hypoxic pulmonary vasoconstriction, and inhibition of hypoxia-induced pulmonary artery cytokine expression when compared with milrinone. To study this, isolated rat pulmonary artery and thoracic aorta rings suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), milrinone, or zaprinast to assess pulmonary artery relaxation, thoracic aorta relaxation, inhibition of hypoxic (pO2 = 30-35 mmHg) pulmonary vasoconstriction, and hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression (reverse transcriptase-PCR). Milrinone and zaprinast resulted in dose-dependent pulmonary artery and aortic relaxation, but zaprinast caused significantly less aortic relaxation compared with milrinone (50.12% +/- 3.36% versus 91.03% +/- 2.97%, P < 0.001). Zaprinast, but not milrinone, significantly inhibited hypoxic pulmonary vasoconstriction (zaprinast, 58.42% +/- 5.37%; milrinone, 77.65% +/- 4.42% versus vehicle: 74.42% +/- 7.54%). Hypoxia-induced upregulation of TNF-alpha and IL-1beta mRNA in pulmonary artery was decreased by zaprinast, but not milrinone, pretreatment. These results suggest that zaprinast, but not milrinone, preferentially vasodilates pulmonary artery over aorta, attenuates hypoxic pulmonary vasoconstriction, and inhibits hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression. Therefore, PDE-5 inhibition may be advantageous in the treatment of pulmonary hypertension.

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.

Aprotinin improves kidney function and decreases tubular cell apoptosis and proapoptotic signaling after renal ischemia-reperfusion.

OBJECTIVE: The purpose of the study was to determine the effects of aprotinin on (1) renal function, (2) apoptosis and apoptotic signaling, and (3) the inflammatory response of the kidney after ischemia-reperfusion injury. METHODS: Male rats underwent a sham procedure or left renal ischemia for 1 hour. Rats were divided into three groups and received no reperfusion, reperfusion for 1 hour, or reperfusion for 24 hours. The animals undergoing ischemia received saline solution alone or aprotinin (60,000 kIU/kg). At the end of the experiment, a sample for serum creatinine was taken and the left kidney was harvested. The kidney was analyzed for expression of tumor necrosis factor alpha, interleukin 1beta, and interleukin 6 (enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction) and activation of p38 mitogen-activated protein kinase, caspase 3, and caspase 8 (Western blot). The kidney was assessed for apoptosis with enzyme-linked immunosorbent assay and by terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick-end labeling staining of tissue slides. RESULTS: Aprotinin significantly decreased the rise in serum creatinine and apoptosis caused by ischemia-reperfusion. Aprotinin significantly reduced interleukin 1 and 6 messenger RNA production and showed a trend toward reducing tumor necrosis factor messenger RNA production after ischemia. Aprotinin also significantly reduced caspase 8 activation and showed a trend toward decreasing p38 mitogen-activated protein kinase activation after 1 hour of reperfusion. CONCLUSION: These results suggest that aprotinin provides protection from renal ischemia-reperfusion injury. They also suggest that aprotinin may do so by affecting apoptotic signaling and inflammatory cytokine production. Aprotinin is a potential therapeutic measure in clinical situations where renal ischemia-reperfusion injury can be anticipated, provided adequate heparinization is possible.

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.

Sexual dimorphism in myocardial tumor necrosis factor-alpha and cardiac function during endotoxin tolerance.

BACKGROUND: Preconditioning is injury-induced protection against subsequent injury and may be induced by a variety of stimuli. Both males and females may be preconditioned; however, if females are relatively protected against the initial insult, is their preconditioning threshold higher? We hypothesized that preconditioning injury threshold differences may exist between genders, which may be associated with differences in myocardial inflammatory monokine production. METHODS: Male and female Sprague-Dawley rats (n=3-5/group) were given intraperitoneal injections of 125 or 500 microg/kg Salmonella typhimurium lipopolysaccharide (ETX) or 0.4 mL normal saline (NS; 154 mmol/L NaCl). After 24 hours, another injection of 500 microg/kg ETX (injury dose) or NS was given, and the animals were incubated an additional 1 or 6 hours. The rats were anesthetized and myocardial function evaluated via the Langendorff perfusion model. Tumor necrosis factor-alpha (TNF-alpha), interleukin-(IL)-1beta, and IL-6 were measured in 1-hour animals via an enzyme-linked immunosorbent assay. Nonpreconditioned rats (PC-) received NS followed by ETX. Preconditioned rats received either 125 microg/kg ETX (PC+125) or 500 microg/kg ETX (PC+500) followed by injury dose ETX. RESULTS: PC+125 and PC+500 males, as well as PC+500 females, were preconditioned and retained cardiac function similar to shams. PC+125 females were not preconditioned with this stimulus and had a decrease in cardiac function similar to PC- rats. Furthermore, PC+125 and PC+500 males, and PC+500 females had decreased release of TNF-alpha after preconditioning, while PC- animals and PC+125 females did not. CONCLUSIONS: Males and females can be preconditioned by endotoxin; however the preconditioning threshold is higher in females than males.

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.

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.

Ethyl pyruvate inhibits hypoxic pulmonary vasoconstriction and attenuates pulmonary artery cytokine expression.

Hypoxic pulmonary vasoconstriction is a common consequence of acute lung injury and may be mediated by increased local production of proinflammatory cytokines. Ethyl pyruvate is a novel anti-inflammatory agent that has been shown to down-regulate proinflammatory genes following hemorrhagic shock; however, its effects on hypoxic pulmonary vasoconstriction are unknown. We hypothesized that ethyl pyruvate would inhibit hypoxic pulmonary vasoconstriction and down-regulate pulmonary artery cytokine expression during hypoxia. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings (n = 8/group) during hypoxia (95% N(2)/5% CO(2)) with or without prior ethyl pyruvate (10 mm) treatment. Following 60 min of hypoxia, pulmonary artery rings were analyzed for tumor necrosis factor-alpha and interleukin-1 mRNA via reverse transcriptase polymerase chain reaction. Ethyl pyruvate inhibited hypoxic pulmonary artery contraction (4.49 +/- 2.32% versus 88.80 +/- 5.68% hypoxia alone) and attenuated the hypoxic up-regulation of pulmonary artery tumor necrosis factor and interleukin-1 mRNA (P < 0.05). These data indicate that (1) hypoxia increases pulmonary artery vasoconstriction and proinflammatory cytokine gene expression; (2) ethyl pyruvate decreases hypoxic pulmonary vasoconstriction and down-regulates hypoxia-induced pulmonary artery proinflammatory cytokine gene expression; and (3) ethyl pyruvate may represent a novel therapeutic adjunct in the treatment of acute lung injury.