Oral arginine reduces gut mucosal injury caused by lipopolysaccharide endotoxemia in rat

BACKGROUND: The objective of this study was to evaluate the effects of lipopolysaccharide (LPS) endotoxemia and enteral arginine (ARG) supplementation on intestinal structural changes, enterocyte proliferation, and apoptosis in rat. METHODS: Male Sprague-Dawley rats, weighing 250-280 g, were divided into three experimental groups: control rats, LPS rats treated with lipopolysaccharide given ip at a dose of 10 mg/kg every 24 h (two injections), and LPS-ARG rats treated with enteral arginine given in drinking water (2%) 72 h before and following injection of LPS. Intestinal structural changes, enterocyte proliferation, and enterocyte apoptosis were determined on day 3 following the first LPS injection. RESULTS: LPS rats demonstrated a significant decrease in bowel weight in duodenum, mucosal weight in duodenum, jejunum, and ileum, mucosal DNA and protein in jejunum and ileum, and villus height in jejunum and ileum compared to control animals. LPS rats also had a significantly lower cell proliferation index in jejunum and ileum and a higher apoptotic index in jejunum and ileum compared to control rats. LPS-ARG animals demonstrated greater duodenal bowel weight, duodenal and ileal mucosal weight, ileal mucosal DNA and protein, ileal villus height, and jejunal and ileal cell proliferation index compared to LPS animals. CONCLUSIONS: LPS endotoxemia impairs the integrity of the gastrointestinal mucosa in rat. Decreased cell proliferation and increased apoptosis may be considered the main mechanisms responsible for the decreased cell mass. Enteral arginine administration decreases the mucosal injury caused by lipopolysaccharide.     

Beneficial effects of oral insulin on intestinal recovery following ischemia-reperfusion injury in rat

BACKGROUND: It has been reported that oral insulin has a trophic effect on intestinal mucosa, but the precise mechanism of its action is still unclear. The purpose of the present study was to investigate the effect of oral insulin on ischemia-reperfusion (IR) intestinal mucosal injury in rat. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent laparotomy (Sham) or IR-intestinal damage by clamping both the superior mesenteric artery and the portal vein for 30 min followed by 24 h reperfusion. IR-INS rats were treated with oral insulin given in drinking water (1U/ml) 48 h before and after IR. Intestinal structural changes, enterocyte proliferation, and enterocyte apoptosis were determined 24 h after IR. Park's score was used for the quantitative assessment of histological change. A non-parametric Kruskal-Wallis ANOVA test was used for statistical analysis with P less than 0.05 considered statistically significant. RESULTS: IR-injury resulted in a significant decrease in bowel weight in jejunum, mucosal weight in jejunum and ileum, villus height in jejunum and ileum, cell proliferation index in jejunum, and ileum compared to sham animals. IR-INS animals demonstrated greater duodenal and jejunal bowel weight, duodenal, jejunal and ileal mucosal weight, jejunal mucosal DNA, jejunal and ileal mucosal protein, jejunal and ileal villus height and crypt depth, jejunal and ileal proliferation index compared to IR-animals. Oral insulin administration induced also a significant decrease in apoptotic index in ileum (1.2 +/- 0.4 versus 2.8 +/- 0.7 TUNEL positive cells/10 villi, P < 0.05) compared to IR-untreated animals. CONCLUSIONS: Oral insulin improves intestinal recovery after IR- injury in rat.     

Effects of oral arginine and glutamine on radiation-induced injury in the rat

BACKGROUND: Exposure of the abdominal region to ionizing radiation is associated with serious untoward symptoms of intestinal dysfunction and some reports indicate that nutrient supplements may reduce these adverse effects. This study was designed to investigate the possible beneficial effects of oral arginine or glutamine supplementation on the radiation-induced tissue injury. MATERIALS AND METHODS: Rats were given one of three feeding regimens: standard diet and water (control group), diet and water containing 2% arginine (arginine group), diet and water containing 2% glutamine (glutamine group) for 3 days prior to radiation. All rats were then subjected to a single does of 1100 cGy to the abdomen. Several serum biochemical parameters and the histologic alterations in different segments of gastrointestinal tract and liver were measured 4 days after irradiation. RESULTS: All the arginine-fed rats developed diarrhea on Day 4 postirradiation, compared to 71% incidence in control rats and 86% in glutamine-fed rats. Serum levels of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in the arginine group were markedly higher than those in other groups. On histological examination, radiation caused more serious damage to various segments of intestine in the arginine-fed rats compared to rats on other feeding regimens. CONCLUSION: These observations seriously question the beneficial effects of arginine and glutamine supplementations on radiation-induced tissue injury.     

Ascorbic acid prevents ischemia-reperfusion injury in the rat small intestine

Ischemia-reperfusion injury by free radicals and lipid peroxides is observed in various organs. Ascorbic acid (AsA) or glutathione (GSH) in various doses (AsA:2, 0.5, 0.1 mmol/kg, GSH:2 mmol/kg) was intraperitoneally administered to male Wistar rats. The entire small intestines were resected just before ischemia, after ischemia, and after 20 min of reperfusion (n = 7–10 at each time point). At each time point, the specimens were subjected to assays of lipid peroxides, GSH, and glutaminase activity of the tissues; they were also examined histologically. In the AsA group, the production of lipid peroxides after reperfusion was significantly suppressed in a dose-dependent manner, and the ratio of oxidized GSH to total GSH was also significantly low. Tissue glutaminase activity decreased to a lesser extent, and the degree of injury was apparently less marked in the AsA group. This study indicates that AsA acts as an antioxidant against peroxidative tissue injury, possibly by scavenging radicals, preserving reduced GSH, and reducing the peroxidative reaction. Received: 21 June 1996 Received after revision: 8 October 1996 Accepted: 12 November 1996     

Normal mesenteric lymph ameliorates acute kidney injury following lipopolysaccharide challenge in mice

Background: The kidney is one of the prior damaged organs subjected to severe infection and sepsis shock. Our previous studies have shown that the normal mesenteric lymph (NML) obtained from healthy dogs could alleviate multiple organ injuries following endotoxic shock. In the current study, we further investigated the beneficial effect of NML from healthy mice on acute kidney injury (AKI) induced by lipopolysaccharide (LPS) in mice. Methods: The mice in LPS and LPS?+?NML groups received an intraperitoneal injection of LPS (35?mg/kg). One hour later, the treatment of NML was performed and kept for 6?h. Then, the renal function indices, renal morphology, the levels of phosphorylation mitogen-activated protein kinases (MAPKs), markers of sensitization to LPS, as well as pro-inflammatory mediators in renal tissue were observed. Results: Intraperitoneal injection of LPS induced an increased level of urea in plasma, lipopolysaccharide-binding protein (LBP), cluster of differentiation 14 (CD14), tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), but no obvious changes in the MAPKs in renal tissue. NML treatment decreased the levels of urea, CD14, TNF-α and IL-6 in mice after LPS injection. Conclusion: The current results indicate that NML alleviates LPS-induced AKI through its attenuation of sensitization to LPS.     

Combined microwave irradiation and intraarticular glutamine administration‐induced HSP70 expression therapy prevents cartilage degradation in a rat osteoarthritis model

The objective of the present study was to investigate the effects of heat stimulation and glutamine (Gln) on the expression of extracellular matrix genes and heat shock protein 70 (HSP70) in rat articular cartilage in vivo and to determine whether HSP70 expression achieved with a combination of microwave (MW) and Gln suppresses osteoarthritis (OA) progression in a rat OA model. Stimulation at 40 W was assumed to be appropriate in the present study, and the effects of heat treatment at this intensity were evaluated. Articular cartilage was collected at 8 h after heat stimulation and/or intraarticular Gln administration, and total RNA was extracted. The expression of HSP70, aggrecan, and type II collagen was quantified using real‐time RT‐PCR. Cartilage samples from the OA model were subjected to hematoxylin and eosin (HE) and safranin O staining. HSP70 and aggrecan expression was greatest in a group receiving both MW and Gln. In the rat OA model, the severity of OA was significantly milder in a group receiving MW and Gln than in the control group. HSP70, stimulated by the combination of MW heat and Gln, may be involved in the suppression of OA progression. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:401–407, 2012     

The effect of growth hormone on gut mucosal homeostasis and cellular mediators after severe trauma

BACKGROUND: Gut mucosal integrity and function is impaired after severe trauma with associated increases in small bowel epithelial cell apoptosis and decreases in cell proliferation. Growth hormone improves gastrointestinal function during chemotherapy and has anabolic effects on protein synthesis. The purpose of this study was to determine whether growth hormone can improve small bowel homeostasis after injury and by which cellular mechanisms these changes occur. MATERIALS AND METHODS: Rats were pair-fed, given a thermal trauma, and received saline (n = 28) or GH (2.5 mg/kg every 24 h, n = 28). Small intestine and serum were taken at 1, 2, 5, and 7 days after injury. Measures were mucosal apoptosis, proliferation, villous morphology, apoptotic, and proliferative mediators, such as Caspases-3, -8, Fas and Fas-Ligand, Bcl-2, and Bcl-x. In addition serum cytokines were determined. RESULTS: Gut epithelial cell apoptosis and proliferation were increased in both groups after the thermal injury (P < 0.05). GH had neither an effect on small bowel epithelial cell apoptosis or proliferation, nor dependent cellular mediators after thermal injury. However, GH significantly improved villous morphology (height and cell number) when compared with controls (P < 0.05). RhGH was found to significantly increase serum TNF-alpha compared to controls (P < 0.05). CONCLUSION: Growth hormone improves small bowel homeostasis after severe trauma independent from small bowel epithelial cell apoptosis or proliferation, probably by increasing the life span.     

Mucosal production of complement C3 and serum amyloid A is differentially regulated in different parts of the gastrointestinal tract during endotoxemia in mice

The effect of endotoxemia and sepsis on mucosal production of the acute-phase proteins complement component C3 and serum amyloid A (SAA) was studied in mice. In addition, the role of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin (EL)-Iβ, and IL-6 on mucosal C3 and SAA production was examined. Endotoxemia was induced by the subcutaneous injection of 250 μg/mouse of lipopolysaccharide. Control mice were injected with corresponding volumes of sterile saline solution. Sepsis was induced by cecal ligation and puncture, and sham-operated mice served as controls. Endotoxemia resulted in increased mucosal C3 levels in all parts of the gastrointestinal tract examined, from the stomach to the colon, with the most pronounced effects noticed in the proximal gastrointestinal tract. The influence of endotoxemia on mucosal SAA production was more differentiated with increased levels noted in the jejunum and ileum, and no changes seen in gastric and colonic mucosa. Sepsis resulted in similar changes in mucosal C3 and SAA levels as seen in endotoxemic mice, except that SAA levels were increased in colonic mucosa of septic mice. Among the cytokines, IL-lβ resulted in the most pronounced changes in mucosal acute-phase proteins. The increase in C3 and SAA levels in the mucosa of the small intestine during endotoxemia was partially blocked by IL-1 receptor antagonist. The results suggest that endotoxemia is associated with increased mucosal C3 production in different parts of the gastrointestinal tract and increased SAA production in the mucosa of the small intestine. Mucosal acute-phase protein synthesis may, at least in part, be regulated by IL-1 β. Supported by a grant from the Shriners of North America. Some of the results reported herein were presented at the Thirty-Eighth Annual Meeting of The Society for Surgery of the Alimentary Tract, Washington, D.C., May 11–14, 1997.     

烫伤大鼠细胞免疫抑制与肠源性内毒素血症的关系

采用大鼠40%TBSAⅢ度烫伤模型,将动物随机分成烫伤对照组和选择性消化道脱污染(SI)D)防治组,探讨烫伤大鼠全身性细胞免疫抑制与肠源性内毒素血症的关系。结果显示,大鼠40%Ⅲ度烫伤后睥细胞对促有丝分裂原增殖应答反应、诱生白介素-2(IL-2)活性及 T 细胞亚群(Th/Ts)比值明显下降。预防性进行 SDD 动物,内毒素血症发生率显著降低,脾细胞增殖应答反应和 IL-2活性的诱生能力均明显恢复(P0.05)。提示烫伤所致肠道细菌/内毒素移位可能与诱发机体细胞免疫功能异常密切相关。SDD 预处理可防止动物细菌/内毒素移位,从而减轻创伤后的免疫抑制。     

肠源性内毒素血症对组织脂多糖结合蛋白mRNA表达的影响

目的探讨烫伤后肠源性内毒素血症对不同组织脂多糖结合蛋白（ＬＢＰ）ｍＲＮＡ表达的影响。方法采用大鼠３５％体表面积Ⅲ度烫伤模型，观察门、体循环内毒素含量及肝、肺、肠、肾等组织ＬＢＰｍＲＮＡ表达的改变。结果烫伤后血浆内毒素水平（门、体循环均值分别为０．７０７ＥＵ／ｍｌ与０．３４２ＥＵ／ｍｌ）及细菌移位率（３７．１％）较伤前值均有显著升高（Ｐ＜０．０１）。同时，肝、肺、肠、肾等组织ＬＢＰｍＲＮＡ表达亦显著增多（Ｐ＜０．０１）。给予杀菌／通透性增加蛋白（ＢＰＩ）治疗后可明显降低门、体循环血浆内毒素水平及肺、肠、肾等组织ＬＢＰｍＲＮＡ表达（Ｐ＜０．０５～０．０１），其中以肠道改变最为显著（治疗组与烫伤组均值分别为０．９９０与１．７２９，Ｐ＜０．０１）。相关分析显示，肺组织ＬＢＰｍＲＮＡ表达与血浆内毒素水平呈显著正相关（ｒ＝０．５９４，Ｐ＜０．０５）。结论创伤后肠源性内毒素血症可显著影响不同组织ＬＢＰｍＲＮＡ的表达，ＬＢＰｍＲＮＡ在局部组织表达增多可能与增敏内毒素血症的组织器官损伤有关。     

烫伤大鼠细胞免疫抑制与肠源性内毒素血症的关系

采用大鼠４０％ＴＢＳＡⅢ度烫伤模型，将动物随机分烫伤对照组和选择性消脱污染防治组，探讨烫伤大鼠全身性细胞免疫抑制与肠源性内毒素血症的关系。结果显示，大鼠４０％Ⅲ度烫伤后脾细胞对促有丝分裂原增殖应答反应、诱生白介素－２（ＩＬ－２）活性及Ｔ细胞亚群（Ｔｈ／Ｔｓ）比值明显下降，预防性进行ＳＯＤ动物，内毒素血症发生率显著降低，脾细胞增殖应答反应和ＩＬ－２活性的诱生能力均明显恢复（Ｐ〈０．０５￣０．０１），     

烫伤大鼠细胞免疫抑制与肠源性内毒素血症的关系

采用大鼠４０％ＴＢＳＡⅢ度烫伤模型，将动物随机分成烫伤对照组和选择性消化道脱污染（ＳＤＤ）防治组，探讨烫伤大鼠全身性细胞免疫抑制与肠源性内毒素血症的关系。结果显示，大鼠４０％Ⅲ度烫伤后脾细胞对促有丝分裂原增殖应答反应、诱生白介素－２（ＩＬ－２）活性及Ｔ细胞亚群（Ｔｈ／Ｔｓ）比值明显下降。预防性进行ＳＤＤ动物，内毒素血症发生率显著降低，脾细胞增殖应答反应和ＩＬ－２活性的诱生能力均明显恢复（Ｐ＜０．０５～０．０１），但外周血中Ｔｈ／Ｔｓ比值与对照组相比差异无显著意义（Ｐ＞０．０５）。提示烫伤所致肠道细菌／内毒素移位可能与诱发机体细胞免疫功能异常密切相关。ＳＤＤ预处理可防止动物细菌／内毒素移位，从而减轻创伤后的免疫抑制     

A novel dehydroepiandrosterone analog improves functional recovery in a rat traumatic brain injury model

The purpose of this study was to investigate the efficacy of a novel steroid, fluasterone (DHEF, a dehydroepiandrosterone (DHEA) analog), at improving functional recovery in a rat model of traumatic brain injury (TBI). The lateral cortical impact model was utilized in two studies of efficacy and therapeutic window. DHEF was given (25 mg/kg, intraperitoneally) at the initial time point and once a day for 2 more days. Study A included four groups: sham injury, vehicle treated (n = 22); injured, vehicle treated (n = 30); injured, pretreated (5-10 min prior to injury, n = 24); and injured, posttreated (initial dose 30 min postinjury, n = 15). Study B (therapeutic window) included five groups: sham injury, vehicle treated (n = 17); injured, vehicle treated (n = 26); and three posttreatment groups: initial dose at 30 min (n = 18), 2 h (n = 23), or 12 h (n = 16) postinjury. Three criteria were used to grade functional recovery. In study A, DHEF improved beam walk performance both with pretreatment (79%) and 30-min posttreatment group (54%; p < 0.01, Dunnett vs. injured vehicle). In study B, the 12-h posttreatment group showed a 97% improvement in beam walk performance (p < 0.01, Dunnett). The 30-min and 12-h posttreatment groups showed a decreased incidence of falls from the beam, which reached statistical significance (p < 0.05, Dunnett). Tests of memory (Morris water maze) and neurological reflexes both revealed significant improvements in all DHEF treatment groups. In cultured rat mesangial cells, DHEF (and DHEA) potently inhibited interleukin-1beta-induced cyclooxygenase-2 (COX2) mRNA and prostaglandin (PGE2) production. In contrast, DHEF treatment did not alter injury-induced COX2 mRNA levels in the cortex or hippocampus. However, DHEF (and DHEA) relaxed ex vivo bovine middle cerebral artery preparations by about 30%, with an IC(50) approximately 40 microM. This was a direct effect on the vascular smooth muscle, independent of the endothelial cell layer. Fluasterone (DHEF) treatments improved functional recovery in a rat TBI model. Possible mechanisms of action for this novel DHEA analog are discussed. These findings suggest an exciting potential use for this agent in the clinical treatment of traumatic brain injury.     

Inosine modulates gut barrier dysfunction and end organ damage in a model of ischemia-reperfusion injury

INTRODUCTION: Gut barrier failure is an important source of morbidity in critically ill patients, and patients undergoing aortic cross-clamp. Inosine, an endogenous purine nucleoside without known side effects, formed from the breakdown of adenosine by adenosine deaminase, has been shown to modify the effects of hypoxia on various tissues, including the heart and the brain. MATERIALS AND METHODS: This study examined the effect of inosine on ischemia-reperfusion-induced gut barrier dysfunction and on the associated lung injury. Twenty-four male Sprague-Dawley rats were divided into three groups. Eight were subjected to 60 min of superior mesenteric artery occlusion followed by 4 h of reperfusion. Eight had 100 mg/kg inosine prior to ischemia-reperfusion and 8 had sham laparotomy with encircling but not occlusion of the superior mesenteric artery. RESULTS: Rats treated with inosine had significantly less gut barrier dysfunction. Rats subjected to SMAO sustained a substantial lung injury and this was attenuated by inosine treatment. Serum cytokine levels were also significantly lower. CONCLUSIONS: We conclude that inosine has a beneficial effect in modulating both gut barrier dysfunction and distant organ injury in response to gut ischemia-reperfusion.     

Glutamine donor pretreatment in rat kidney transplants with severe preservation reperfusion injury

BACKGROUND: Glutamine (GLN) has been shown to confer cytoprotection by enhancing endogenous heat shock protein (HSP) expression. We hypothesized that GLN donor pretreatment protects rat renal grafts against severe preservation reperfusion injury (PRI). MATERIALS AND METHODS: GLN (0.75 g/kg) or saline was administered i.p. to male donor rats 24 h and 6 h before donor nephrectomy. Kidneys (n = 6/group) were cold-stored in UW solution for 40 h and transplanted into bilaterally nephrectomized syngeneic recipients. Grafts were removed after 24 h. Renal HSP 70 expression was determined by Western blotting. Graft function was assessed by serum creatinine. Renal cross sections were microscopically examined for acute tubular necrosis, apoptosis, tubular proliferation, and macrophage infiltration. RESULTS: GLN donor pretreatment significantly increased intragraft HSP 70 expression. Serum creatinine was not different between groups: 2.6 +/- 0.2 mg/dL (saline) versus 2.7 +/- 0.5 mg/dL (GLN). Both treatment groups showed severe tubular damage with significantly less papillary necrosis in the GLN group (P < 0.05). GLN significantly reduced the number of apoptotic tubular cells in the cortex, medulla, and papilla (P < 0.001 versus saline). Postinjury tubular proliferation, measured by PCNA antigen expression, and intragraft macrophage infiltration was not influenced by GLN. CONCLUSIONS: In rat renal grafts suffering severe PRI pharmacological preconditioning with GLN attenuates early structural damage, especially tubular cell apoptosis. Stimulation of renal HSP 70 expression could be an important mechanism of GLN-induced cytoprotection. Our findings may have implications for the treatment of delayed graft function in recipients of marginal donor kidneys.     

Specific inhibition of iNOS decreases the intestinal mucosal peroxynitrite level and improves the barrier function after thermal injury

Failure of GI tract mucosa to act as a barrier against bacterial translocation (BT) has been proposed as a potential source of sepsis and subsequent multiple organ failure post thermal injury. Nitric oxide (NO) is an inorganic radical produced by NO synthase (NOS) from -arginine. Gut mucosal constitutive NOS (cNOS) provides protection for itself. In contrast to cNOS, inducible NOS (iNOS) releases far greater amounts of NO, promotes oxidative reactions and is responsible for tissue injury. Peroxynitrite formed by the rapid reaction between superoxide and NO, is a toxic substance that contributes to tissue injury in a number of biological systems. This study was designed to investigate the effect of iNOS specific inhibitor S-methylisothiourea (SMT) on the postburn intestinal mucosal barrier function and the possible mechanism of SMT's action. Female SPF Sprague–Dawley rats underwent 35% total body surface area (TBSA) or sham burn. Either SMT or the same volume of saline was given (5 mg/kg, i.p. q 12 h) for 2 days to assess the effect of iNOS inhibition. On postburn day 2, the intestinal mucosal cNOS and iNOS activity were assayed by using Griess' reagent, the mesenteric lymph node (MLN), spleen and liver were collected and cultured for BT assay and the cellular localization of nitrotyrosine, a marker for peroxynitrite activity, was examined by immunostaining. After thermal injury in rats, administration of SMT for 2 days decreased the intestinal mucosal iNOS activity/tNOS activity ratio and the BT incidence. Nitrotyrosine immunostaining of the intestinal mucosa showed a decrease in the SMT-treated group. These findings suggest that SMT, a specific inhibitor for iNOS improves the barrier function after burn by suppression of the intestinal mucosal iNOS activity. The decrease in NO production resulted in decreased formation of peroxynitrite and subsequently decreased damage of mucosal tissue.     

Effects of progesterone on intestinal inflammatory response, mucosa structure alterations, and apoptosis following traumatic brain injury in male rats

BACKGROUND: Traumatic brain injury (TBI) can induce a persistent inflammatory response, histopathological changes, and apoptosis in the gut. Progesterone given after TBI has been shown to reduce the cerebral inflammation and neuronal apoptosis in the brain. However, the effects of progesterone on the inflammatory response, structure alterations, and apoptosis in the intestinal mucosa following TBI has not been investigated. MATERIALS AND METHODS: Right parietal cortical contusion in male rats was made by using the weight-dropping method. Rats were given 0 or 16 mg/kg injections of progesterone at postinjury at 1 and 6 hours and on days 1, 2, 3, 4, and 5. Gut samples were extracted at 5 days after trauma. We measured the concentrations of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay; intercellular adhesion molecule-1 expression by immunohistochemistry; intestinal mucosal morphological changes by histopathological study and electron microscopy; and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining. RESULTS: Administration of progesterone following TBI could decrease the intestinal concentrations of IL-1beta and tumor necrosis factor-alpha, but not IL-6. The level of intercellular adhesion molecule-1 expression in the gut was down-regulated by progesterone. TBI-induced damages of gut structure and apoptosis were attenuated after progesterone injections. CONCLUSIONS: The results of the present study suggest that post-TBI progesterone administration could suppress the intestinal inflammation, protect the intestinal mucosal structure, and reduce the mucosa apoptosis.     

Olprinone improves diaphragmatic contractility and fatigability during abdominal sepsis in a rat model

BACKGROUND: Respiratory failure with diaphragmatic fatigability is common in patients suffering sepsis or septic shock. However, the development and progress of diaphragmatic fatigability remains poorly understood, and no method has been established to treat fatigability. In this study, we hypothesize that neutrophil activation contributes to the development of diaphragmatic fatigability. We also sought to investigate whether a phosphodiesterase inhibitor, olprinone, improves diaphragmatic fatigability associated with abdominal sepsis and inhibits an increase in myeloperoxidase activity in diaphragmatic muscle. METHODS: Male Wistar rats were randomly assigned to a sham group, coecal legation perforation group (CLP), and a phosphodiesterase inhibitor (PDE) pretreated group. At 16 h after surgical procedure, the left hemidiaphragm was removed for the measurement of diaphragmatic contractility and fatigability. In addition, for the measurement of serial changes in myeloperoxidase activity, the right hemidiaphragm was also removed at 4, 8 or 16 h after the surgical procedure in each group. RESULTS: In a septic model involving rats, we observed that diaphragmatic muscles were fatigable and myeloperoxidase activity increased. We also demonstrated that intraperitoneal administration of olprinone improves diaphragmatic fatigability and inhibits an increase in myeloperoxidase activity induced by abdominal sepsis. CONCLUSION: Olprinone represents a potential therapy for cases of respiratory failure with diaphragmatic fatigability resulting from inhibition of neutrophil activation.