Prevention of Postoperative Peritoneal Adhesions by Administration of Estrogen

Aim: Postoperative abdominal adhesions represent one of the most common causes of intestinal obstruction in surgical patients. In this study, the effects of intraperitoneal administration of estrogen on the development of postoperative intraabdominal adhesions and peritoneal leucocytes in a rat adhesion model were investigated. Methods: Sixty Wistar albino rats were divided into three groups. Group 1 (control group) had their abdomen closed after surgery without administration of any material or drug. Group 2 (saline group) received 2 ml of 0.9% NaCl, and group 3 (estrogen group) animals received a single intraperitoneal dose of 2 cc (1 mg) estrogen (Estradiol propionate, 50.000U, Akrofilline®, Biofarma, Turkey). All the groups were exposed to the same adhesion-creating procedure (Swolin K. Experimental studies on the prevention of intra-abdominal adhesions. Studies on rats with an emulsion of lipid and prednisolone. Acta Obstet Gynecol Scand. 1966;45:473–498.). After 7–42 days, all animals were sacrificed. Adhesions were scored and peritoneal leucocytes were counted. Results: The adhesion formation and peritoneal leucocyte count of the estrogen group were significantly less than the control and saline groups and a statistically significant difference was determined in comparison of those groups (p <. 05). Conclusion: We concluded that intraperitoneal estrogen decreases the incidence of postoperative intraabdominal adhesion formation in rat adhesion model.     

Source of Reactive Oxygen Species in Anti-Thy1 Nephritis

In proliferative glomerulonephritis, both macrophages and mesangial cells generate reactive oxygen species (ROS), contributing to the development of glomerular injury. We have attempted to determine which cell produces ROS during anti-Thyl nephritis (ATN) in rats. The generation of ROS was studied using lutninol amplified chemiluminescence (GCL) on isolated glomeruli. Immunohistochemical studies used avidin-biotin complex (ABC) to label macrophages and mesangial cells. Immediately after ATN induction, mesangiolysis and infiltration with ED-1 positive cells (referred to as macrophage) was noted with a peak at day 1. After day 4, mesangial proliferation appeared with a decrease of the ED-1 positive cells and a prominent increase of PCNA positive cells (regarded as mesangial cells). In the early phase of ATN, GCL, reflecting ROS generation, increased along with the appearance of ED-1 positive cells. GCL subsequently decreased as mesangial cells increased. This suggested that macrophage were the principal participants in ROS generation in the early phase of ATN although mesangial cells cannot be completely disregarded in the generation of ROS and development of glomerular injury.     

A New Approach for Decreasing Postoperative Peritoneal Adhesions: Preventing Peritoneal Trauma with Soybean Oil

Background: Covering peritoneal surfaces with soybean oil may decrease peritoneal adhesions by preventing peritoneal trauma. Method(s): Forty female albino Wistar rats were divided into four equal groups. In Group 1, soybean oil only (0.1 ml) was injected into the peritoneal cavity. In Group 2, an untreated adhesion model was generated. In Group 3, an adhesion model was generated, followed by covering the area with soybean oil (0.1 ml). In Group 4, the area was first covered with soybean oil (0.1 ml) followed by generation of an adhesion model. All rats were sacrificed on postoperative day 10, and adhesions were scored. Results: The mean macroscopic adhesion scores in Groups 1, 2, 3, and 4 were 0.0 ± 0.0, 2.90 ± 0.21, 1.90 ± 0.94, and 0.50 ± 0.71, respectively. The Group 4 score differed significantly from that of Group 2 (p <. 001), but was not different from that of Group 1 or 3 (p >. 05). Discussion: Soybean oil can effectively decrease adhesion formation if applied before peritoneal trauma.     

活性氧与勃起功能障碍

男性勃起功能障碍(ED)是男科常见疾病之一,当前全世界有15200万男性受到ED的困扰。近年来已经认识到活性氧(reactive oxygen species,ROS)在ED中起重要作用。本文总结近年来ROS在ED中作用的研究进展,并阐述ROS与ED中各种危险因子的关系以及抗氧化治疗进展,为开发治疗ED的药物提供新的方向。     

Reactive Oxygen Species Play a Biphasic Role in Brain Ischemia

Objective: Reactive oxygen species (ROS) are the essential mechanism involving in the ischemic process. Due to their complex characteristics, the precise effects of ROS on post-ischemic neurons remain uncertain. This study aimed to investigate the potential role of ROS in brain ischemia. Methods: Dynamic ROS levels in the perifocal cortex were evaluated after right middle cerebral artery occlusion (MCAO) of SD rats. Furthermore the role of ROS was assessed following delayed treatment with the ROS scavenger dimethylthiourea (DMTU) after brain ischemia. Results: ROS levels markedly increased at 1 hr after reperfusion and then gradually decreased as the post-reperfusion time interval increased. ROS levels reached their lowest point at 3 days after reperfusion before increasing and showing a second peak at 7 days after reperfusion. ROS levels negatively correlated with neurological function scores. Delayed DMTU treatment after stroke worsened neurological outcomes, decreased microvessel density and inhibited stress-activated protein kinase activation. Conclusion: ROS may play a biphasic role in cerebral ischemia. Namely, ROS may induce damage during the injury phase of brain ischemia and participate in improving neurological function during the recovery phase.     

AGE与RAGE相互作用通过活性氧引起足细胞凋亡

目的：探讨晚期糖基化终末产物（AGE）对足细胞凋亡的影响,及氧化应激在其中的作用。方法：小鼠足细胞株由美国纽约西奈山医学院Peter Mundel教授馈赠。用钙磷脂结合蛋白Ⅴ-荧光异硫氰酸盐（FITC）和碘化物（PI）标记细胞,采用荧光激活细胞分类（FACS）法来计数凋亡和坏死的足细胞。Dharmacon On TargetPlus SMARTpool si RNA试剂和Amaxa RNAi nucleofection试剂盒成功转染si RNA到足细胞。绿荧光蛋白载体证明转染的有效性,分别采用Western Blot和实时定量PCR（RT-PCR）方法来检测si RNA转染足细胞后AGE受体蛋白（RAGE）靶基因蛋白质和mRNA的表达。用LS50B型荧光分光光度计测活性氧,根据波长485nm在530nm发射的荧光来判断活性氧（ROS）的产生。观察活性氧的清除剂N-乙酰基-半胱氨酸（NAC）能否减少AGE-BSA诱导的足细胞凋亡。结果：AGE引起足细胞的凋亡呈剂量依赖性,随AGE浓度的增大,凋亡的发生率逐渐升高;RAGE siRNA能减少60%~70%RAGE mRNA和蛋白质的表达;ROS的清除剂NAC可明显减少AGE-BSA引起的ROS的产生和足细胞凋亡。结论：AGE与RAGE作用后活性氧产生增加,活性氧的增加可能是AGE引起足细胞凋亡的途径之一,可通过抗氧化减少ROS的产生延缓糖尿病肾病的进展。     

Oxidized Regenerated Cellulose Sheets in Postoperative Intrathoracic Adhesions

Adhesiolysis is often necessary in intrathoracic adhesion during ipsilateral repeat lung resection. This procedure has a risk of surgical complications, including unintentional intraoperative damage of the pulmonary vessels or lung parenchyma. We used an oxidized regenerated cellulose (ORC) sheet to prevent intrathoracic adhesion after lung resection in 55 patients. The sheet was placed on the surface of the resected region and on the lung surface under the wound. No major postoperative complications were observed. Three cases underwent ipsilateral thoracic surgery for the treatment of lung malignancies, and there were no intrathoracic adhesions around the ORC sheet-covered area.     

Reactive Oxygen Species Independent Cytotoxicity Induced by Radiocontrast Agents in Tubular Cells (LLC-PK1 and MDCK)

Purpose. Radiocontrast agents (RAs) cause renal tubular damage by hemodynamic imbalance, which could cause hypoxic stimulus and direct cytotoxicity. However, reactive oxygen species (ROS) could be an important factor in RAs' direct cytotoxicity. This study investigated the involvement of ROS in deleterious effects produced by RAs on normoxic and hypoxic renal tubular cells. Materials and Methods. LLC-PK1 and MDCK were exposed to diatrizoate and ioxaglate in normoxic and hypoxic conditions. Apoptotic and necrotic cell death were assessed by acridine orange/ethidium bromide and annexin V methods. Hydrogen peroxide, superoxide anion, and malondialdehyde levels were analyzed by, respectively, 2′,7′-dichlorofluorescein, luminal, and thiobarbituric acid. Antioxidant agents were used to prevent cellular RAs damage. Results. Diatrizoate and ioxaglate decreased cellular viability in both cells, and this effect was enhanced by hypoxic conditions. Diatrizoate induced more injury than ioxaglate to both cell lines. LLC-PK1 underwent necrosis, while MDCK cells underwent apoptosis when exposed to diatrizoate. These results could not be attributed to an increase in osmolality. RAs did not increase hydrogen peroxide, superoxide anion or malondialdehyde levels in both cells. Additionally, N-acetyl-L-cysteine (NAC), ascorbic acid, α-tocopherol, glutathione, β-carotene, allopurinol, cimetidine, and citric acid did not protect cells against RAs damage. Surprising, NAC increased the cellular damage induced by ioxaglate in the both cell lines. Conclusion. The present study shows that RAs induce damage in cultured tubular cells, especially in hypoxic conditions. ROS were not involved in the observed RAs' cytotoxicity, and NAC increased ioxaglate-induced tubular damage.     

Bacterial Studies of Peritoneal Cavity and Postoperative Surgical Wound Drainage Following Perforated Appendix in Children

This study reports bacterial specimens obtained from 112 children presenting with a ruptured appendix. Additional samples were studied from 11 of these patients who developed a postoperative surgical draining wound. Bacterial growth occurred in 100 peritoneal fluid specimens. Anaerobic bacteria alone were present in 14 specimens, aerobes alone in 12, and mixed aerobic an anerobic flora in 74 specimens. There were 144 aerobic isolates (1.4 per specimen). The predominant isolates were: E. coli (57 specimens); alpha-hemolytic steptococcus (16 specimens); gamma-hemolytic streptococcus (15 specimens); Group D streptococcus (12 specimens); and P. aeruginosa (9 specimens). There were 301 anaerobic isolates (three per specimen). The predominant isolates were: 157 Bacteroides spp. (including 92 B. fragilis group and 26 B. melaninogenicus group); 62 gram-positive anaerobic cocci (including 30 Peptococcus sp.; 29 Peptostreptococcus sp.); 27 Fusobactenium sp.; and 16 Clostridium sp. B. fragilis and Peptococcus sp. occurred in 23 patients. Beta lactamase production was detectable in 98 isolates recovered from 74 patients. These included all isolates of B. fragilis and six of the 23 Bacteroides sp. Forty-nine organisms (16 aerobic and 33 anaerobic) were recovered from the draining wounds. The predominant organisms were: B. fragilis (8 specimens); E. coli (6 specimens); Peptostreptococcus sp. (5 specimens); and three specimens each of P. aeruginosa and Peptococcus sp. Most of these isolates were also recovered from the peritoneal cavity of the patients. These findings demonstrate the polymicrobial aerobic and anaerobic nature of peritoneal cavity and postoperative wound flora in children with perforated appendix, and demonstrate the presence of beta lactamase-producing organisms in three-fourths of the patients.     

Oral Fluvastatin Reduces the Severity of Peritoneal Adhesions in Rats

Background: The aim of the study was to investigate the effect of fluvastatin on peritoneal adhesion formation.

Methods: 48 female Wistar-albino rats weighing 200–220 g were divided into four groups each containing 12 rats. Group I was sham, Group II was the control group, while Group III was given 10 mg/kg/day (28 days) oral fluvastatin. In Group IV, 10 mg/kg fluvastatin was administered intraperitoneally at the time of laparotomy but the rats died from that dose. After laparotomy on day 14, caecal serosal abrasions and punctuate haemorrhagies were performed. On day 28, laparotomies were repeated. Adhesions were graded and tissue samples were taken from incisions and adhesions. Hydroxyproline contents representing adhesions were measured quantitatively. On the 28th day, blood samples were taken to measure the tissue-type plasminogen activator (t-PA) activity.

Results: There were significant differences between the groups for adhesion severity (p < 0.0001), hydroxyproline content and t-PA activity of the adhesions (p < 0.0001). Analysis of the grading of adhesions documented significant differences between all groups. When the hydroxyproline content and t-PA activity of the adhesions was analyzed, there were significant differences between groups II, I and III, but the difference between group I and group III was not statistically significant.

Conclusions: The data presented in this study demonstrate that the oral administration of the HMG-CoA reductase inhibitor fluvastatin reduced intra-abdominal adhesion formation.     

Mitochondrial Reactive Oxygen Species Are Obligatory Signals for Glucose-Induced Insulin Secretion

OBJECTIVE—Insulin secretion involves complex events in which the mitochondria play a pivotal role in the generation of signals that couple glucose detection to insulin secretion. Studies on the mitochondrial generation of reactive oxygen species (ROS) generally focus on chronic nutrient exposure. Here, we investigate whether transient mitochondrial ROS production linked to glucose-induced increased respiration might act as a signal for monitoring insulin secretion.RESEARCH DESIGN AND METHODS—ROS production in response to glucose was investigated in freshly isolated rat islets. ROS effects were studied using a pharmacological approach and calcium imaging.RESULTS—Transient glucose increase from 5.5 to 16.7 mmol/l stimulated ROS generation, which was reversed by antioxidants. Insulin secretion was dose dependently blunted by antioxidants and highly correlated with ROS levels. The incapacity of β-cells to secrete insulin in response to glucose with antioxidants was associated with a decrease in ROS production and in contrast to the maintenance of high levels of ATP and NADH. Then, we investigated the mitochondrial origin of ROS (mROS) as the triggering signal. Insulin release was mimicked by the mitochondrial-complex blockers, antimycin and rotenone, that generate mROS. The adding of antioxidants to mitochondrial blockers or to glucose was used to lower mROS reversed insulin secretion. Finally, calcium imaging on perifused islets using glucose stimulation or mitochondrial blockers revealed that calcium mobilization was completely reversed using the antioxidant trolox and that it was of extracellular origin. No toxic effects were present using these pharmacological approaches.CONCLUSIONS—Altogether, these complementary results demonstrate that mROS production is a necessary stimulus for glucose-induced insulin secretion.Elucidating the mechanisms by which pancreatic β-cells couple glucose sensing to insulin secretion, a vital process in energy homeostasis, is of prime importance. Although ATP production is considered the main mitochondrial signal, detailed studies show that insulin secretion cannot be restricted to ATP synthesis, and numerous experimental clues show that additional mitochondrial factors involved in glucose-secretion coupling are necessary, although not yet identified (1).Transient increases in glucose metabolism generate NADH and FADH₂, leading rapidly to increased superoxide anion (O₂^·) production; obligatorily associated with the respiratory chain function, superoxide anion will be converted into H₂O₂ (2). This production of mitochondrial reactive oxygen species (mROS)—transient because H₂O₂-inactivating enzymes rapidly quench it before a damage to the physiological conditions of the cell occurs—is now recognized as an intracellular messenger (3,4). These features make mROS a good candidate for rapidly regulating pathways that depend directly on metabolic fluxes. Based on such a view, we recently demonstrated that mROS production is required for hypothalamic glucose and lipid sensing (5,6). These results lead us to speculate that O₂^· might operate more generally in nutrient-sensitive cells and also to look for the role of mROS as a signal involved in glucose-stimulated insulin secretion (GSIS). Recently, a study revealed that H₂O₂ is effectively a signal of GSIS (7). Here, we provide clues that glucose-induced mitochondrial O₂^· production is an obligatory stimulus for insulin secretion.     

Expression of Inducible and Endothelial Nitric Oxide Synthases, Formation of Peroxynitrite and Reactive Oxygen Species in Human Chronic Renal Transplant Failure

Nitric oxide (NO.) is produced by NO synthases (NOS) and can interact with reactive oxygen species (ROS) to form peroxynitrite, which induces protein damage by formation of nitrotyrosine. NO. has a promotional effect on acute rejection. To investigate the role of NO. during chronic renal transplant failure (CRTF), we studied the expression of eNOS and iNOS in conjunction with H2O2 production and the formation of nitrotyrosines. Nephrectomy material from 10 patients and 10 control kidneys was used in this study. Expression of iNOS, eNOS, nitrotyrosine and the presence of ROS-producing cells and macrophages were determined using immunohistochemistry. INOS expression in nonsclerosed glomeruli and interstitium was significantly increased in patients with CRTF (p < 0.05). Glomerular eNOS expression was decreased in patients with CRTF compared with glomeruli of control kidneys (p < 0.01). Nitrotyrosine and ROS positive cells were significantly increased in CRTF in the interstitium (p < 0.05), but not in glomeruli. In summary, we found a marked interstitial increase in iNOS protein expression together with a decrease in glomerular eNOS expression in CRTF patients, associated with a significant increment in ROS and nitrotyrosine-positive cells in the interstitium. Our results suggest that loss of NO. production by glomerular eNOS in conjunction with an increased NO. production by interstitial iNOS, together with the formation of ROS and nitrotyrosine, is involved in the pathogenesis of CRTF.     

Hyperglycemia-Induced Reactive Oxygen Species Increase Expression of the Receptor for Advanced Glycation End Products (RAGE) and RAGE Ligands

OBJECTIVE

RAGE interacts with the endogenous ligands S100 calgranulins and high mobility group box 1 (HMGB1) to induce inflammation. Since hyperglycemia-induced reactive oxygen species (ROS) activate many pathways of diabetic tissue damage, the effect of these ROS on RAGE and RAGE ligand expression was evaluated.

RESEARCH DESIGN AND METHODS

Expression of RAGE, S100A8, S100A12, and HMGB1 was evaluated in human aortic endothelial cells (HAECs) incubated in normal glucose, high glucose, and high glucose after overexpression of either uncoupling protein 1 (UCP1), superoxide dismutase 2 (SOD2), or glyoxalase 1 (GLO1). Expression was also evaluated in normal glucose after knockdown of GLO1. Expression was next evaluated in high glucose after knockdown of nuclear factor (NF)-κB p65 (RAGE) and after knockdown of activated protein-1 (AP-1) (S100A8, S100A12, and HMGB1), and chromatin immunoprecipitation (ChIP) was performed ± GLO1 overexpression for NFκB p65 (RAGE promoter) and AP-1 (S100A8, S100A12, and HMGB1 promoters). Finally, endothelial cells from nondiabetic mice, STZ diabetic mice, and STZ diabetic mice treated with the superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) were evaluated.

RESULTS

High glucose increased RAGE, S100A8, S100A12, and HMGB1 expression, which was normalized by overexpression of UCP1, SOD2, or GLO1. GLO1 knockdown mimicked the effect of high glucose, and in high glucose, overexpression of GLO1 normalized increased binding of NFκB p65 and AP-1. Diabetes increased RAGE, S100A8, and HMGB1 expression, and MnTBAP treatment normalized this.

CONCLUSIONS

These results show that hyperglycemia-induced ROS production increases expression of RAGE and RAGE ligands. This effect is mediated by ROS-induced methylglyoxal, the major substrate of glyoxalase 1.The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with a number of endogenous ligands in normal physiology, playing a homeostatic role in lung development, osteoclast differentiation, innate immunity, and inflammatory cell recruitment and adhesion (1–3). However, conditions such as diabetes disturb homeostasis, increase RAGE expression (4), increase advanced glycation end product formation, and cause release of intracellular calcium binding molecules, the S100 calgranulins (5–7), and the DNA binding protein amphoterin, or high mobility group box 1 (HMGB1), which act as danger signals, called alarmins, that bind to RAGE with high affinity and activate immune cells and vascular endothelium (1,8,9). RAGE signaling stimulates a host of proinflammatory events (1,3). Normally, these appear to play an important role in acute inflammation. In contrast, when responding to persistent elevations of endogenous ligands, RAGE signaling promotes chronic inflammation. Such chronic inflammation plays a major role in the development of diabetic complications, including atherosclerosis (10–12).Because hyperglycemia-induced reactive oxygen species (ROS) activate many pathways of diabetic tissue damage, including intracellular AGE formation (13,14), the effect of these ROS on RAGE and RAGE ligand expression was evaluated. Although a large number of S100 proteins have been shown to interact with RAGE in cell-based assays (15), S100A8 and S100A12 were selected for study because these proteins are found in high concentrations in inflamed tissue, and they exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo (9).     

The Preventive Effect of Rofecoxib in Postoperative Intraperitoneal Adhesions

Background: Previous studies showed that nonsteroidal anti-inflammatory (NSAi) drugs suppressed prostaglandin synthesis and were able to prevent adhesion formation following surgical trauma to the peritoneum. The selective suppression innammatory cascade may prevent adhesion formation. Therefore, we planned this study to experimentally evaluate the effects of Rofecoxib, the selective cyclo-oxygcnase-2 inhibitor, in postoperative intraperitoneal adhesions in an animal model.

Methods: Male Sprague-Dawley rats were divided into three groups of 10. All rats underwent midline laparotomy under ketamine anaesthesia (25 mg/kg im). In group 1 (n = 10), the sham operation group (SG) ; abdominal walls were closed without any process after 2 minutes. In Group 2 (n = 10), the control group (CG) ; standard serosal damage was constituted and the abdominal wall was closed. In group 3 (n = 10), the COX-2 group (COXG), after serosal damage, the abdominal wall was closed. A 12 mg/kg/day dose of was given orally to the rats during one week. On the 7th postoperative day, all rats were sacrificed and intra-abdominal adhesions were evaluated both macroscopically and microscopically.

Results: Macroscopically, no serious adhesion formations were seen in the SG. Multiple adhesion format ions of the CG were significantly more than those of the SG (p < 0.0001). It was determined that adhesions of the COXG diminished (p < 0.0001) when macromorphological adhesion scale results of the COXG were compared with those of the CG. The adhesion scores of the CG were compared microscopically with those of the COXG and granulation tissue formation and fibrosis in the COXG were found to be significantly less than those of the CG (respecti vely p = 0.002, p < 0.0001).

Conclusions: We were of the opinion that Rofecoxib, the selective cyclo-oxygenase inhibitor, was effective in the prevention of postoperative peritoneal adhesions.     

The Significance of Testicular Reactive Oxygen Species on Testicular Histology in Infertile Patients

This study was designed to investigate the relationship between the effects of testicular reactive oxygen species (ROS) levels and testicular histology on infertile patients with the aid of xanthine oxidase system and testicular tissue malondialdehyde levels. Forty patients with idiopathic infertility constituted our study group. Bilateral testicular biopsies were performed and spermatogenesis was assessed histopathologically. Patients were divided into 4 groups according to spermatogenic pattern (normal spermatogenesis; hypospermatogenesis; maturation arrest; Sertoli cell only syndrome). Testicular tissue xanthine oxidase and malondialdehyde (MDA) concentrations were analyzed in each sample by spectrophotometric assay and thiobarbituric acid reaction assay, respectively. Testicular tissue MDA and xanthine oxidase concentrations were not statistically different in patients having normal spermatogenesis, with respect to Sertoli cell only syndrome, maturation arrest and hypospermatogenesis, respectively. As a result of our study we think that there are still some factors other than ROS which may be important contributors to spermatogenetic injury that need to be examined.     

A Novel Method for Evaluating Postoperative Adhesions in Rats

Purpose/Aim: Postoperative adhesions remain an undesirable and commonly symptomatic side effect of abdominopelvic surgeries. Animal models of postoperative adhesions typically yield heterogeneous adhesions throughout the abdominal cavity and are not easily quantified. Here we present a novel method of postoperative adhesion assessment and report its reliability and measurement error. Materials and Methods: A model of cecal abrasion with partial sidewall attachment was performed on female rats. After 1, 2, 4, or 7 days of recovery, the rats were euthanized and their abdominopelvic cavities were systematically evaluated for postoperative adhesions. The necropsy was recorded through the surgical microscope. Four raters were trained to use a ballot to capture key factors of the adhesions as they viewed the recordings. Their ratings were compared for measurement error and reliability (using Bland-Altman plots and intraclass correlation coefficients, respectively) and for the ability to discriminate differences in experimental groups. A subset of the data was analyzed to determine practical utility. Results: The rating system was shown to have low measurement error and high inter-rater reliability for all parameters measured. Applied practically, the system was able to discriminate groups in a manner that was expected. Conclusions: We have developed and validated a rating system for postoperative adhesions and shown that it can detect group differences. This method can be used to quantify postoperative adhesions in rodent models.     

Reactive Oxygen Species Scavengers Attenuate Endotoxin-induced Impairment of Hypoxic Pulmonary Vasoconstriction in Mice

Background: Sepsis and endotoxemia attenuate hypoxic pulmonary vasoconstriction (HPV), thereby impairing systemic oxygenation. Reactive oxygen species (ROS) are implicated in the pathogenesis of sepsis-induced lung injury. The authors investigated whether treatment with scavengers of ROS prevents impairment of HPV in mice challenged with endotoxin.

Methods: The pulmonary vasoconstrictor response to left mainstem bronchus occlusion (LMBO) was studied in anesthetized mice 22 h after an intraperitoneal challenge with saline solution or 10 mg/kg Escherichia coli endotoxin. In some mice, challenge with saline solution or endotoxin was followed after 1 h with intraperitoneal or intratracheal administration of the ROS scavengers N-acetylcysteine or EUK-8. Myeloperoxidase activity and nitric oxide synthase-2 gene expression were measured in lung tissues.

Results: The LMBO increased left pulmonary vascular resistance by 106 +/- 24% in saline-challenged control mice but by only 23 +/- 12% (P < 0.05) in endotoxin-challenged mice. Intraperitoneal administration of N-acetylcysteine or EUK-8 1 h after endotoxin challenge attenuated the endotoxin-induced impairment of HPV (58 +/- 6% and 68 +/- 10%, respectively; both P < 0.05 vs. endotoxin-challenged mice). Intratracheal administration of ROS scavengers 1 h after endotoxin challenge was equally effective but required lower doses than systemic treatment. Administration of the ROS scavengers 22 h after endotoxin challenge did not restore HPV.