Granisetron protects polymicrobial sepsis-induced acute lung injury in mice

Sepsis is a serious condition with a high mortality rate worldwide. Granisetron is an anti-nausea drug for patients undergoing chemotherapy. Here we aimed to identify the novel effect of granisetron on sepsis-induced acute lung injury (ALI). Our results showed that mice treated with granisetron displayed less severe lung damage than controls. Granisetron administration reduced pulmonary neutrophil recruitment after CLP. Moreover, the expressions of Cxcl1 and Cxcl2 were diminished in the presence of granisetron in THP-1 macrophages after lipopolysaccharide exposure. Additionally, granisetron could inhibit the activation of p38 MAPK and NLRP3 inflammasome both in vivo and in vitro. Collectively, granisetron protects against sepsis-induced ALI by suppressing macrophage Cxcl1/Cxcl2 expression and neutrophil recruitment in the lung.     

Map kinase phosphatase 5 protects against sepsis-induced acute lung injury

Mitogen-activated protein kinases (MAPKs) play a critical role in inflammation. Although activation of MAPK in inflammatory cells has been studied extensively, much less is known about the inactivation of these kinases. MAPK phosphatase 5 (MKP5) is a member of the dual-specificity phosphatase family that dephosphorylates activated MAPKs. Here we report that MKP5 protects sepsis-induced acute lung injury. Mice lacking MKP5 displayed severe lung tissue damage following LPS challenge, characterized with increased neutrophil infiltration and edema compared with wild-type (WT) controls. In response to LPS, MKP5-deficient macrophages produced significantly more inflammatory factors including inflammatory cytokines, nitric oxide, and superoxide. Phosphorylation of p38 MAPK, JNK, and ERK were enhanced in MKP5-deficient macrophages upon LPS stimulation. Adoptive transfer of MKP5-deficient macrophages led to more severe lung inflammation than transfer of WT macrophages, suggesting that MKP5-deficient macrophages directly contribute to acute lung injury. Taken together, these results suggest that MKP5 is crucial to homeostatic regulation of MAPK activation in inflammatory responses.     

Ibuprofen attenuates plasma tumor necrosis factor activity during sepsis-induced acute lung injury.

Plasma tumor necrosis factor (TNF) activity, cardiac index, extravascular lung water, systemic and pulmonary arterial pressures, pulmonary vascular resistance index, and arterial PO2 were monitored for 300 min in four groups of anesthetized pigs: saline-infused animals (n = 5), saline-infused animals given ibuprofen (12.5 mg/kg iv) at 0 and 120 min (n = 4), animals infused for 60 min with live Pseudomonas aeruginosa (Ps, 5 x 10(8) organisms/ml at 0.3 ml.20 kg-1.min-1, n = 6), and animals infused for 60 min with Ps plus ibuprofen administered at 0 and 120 min (n = 4). Infusion of Ps induced significant elevations (greater than 4-fold increase in units/ml of TNF by 60 min, P less than 0.05) in plasma TNF activity (L929 cytolysis assay) and alterations (P less than 0.05) in all hemodynamic and pulmonary parameters within 30-60 min. Ibuprofen administration in sepsis significantly decreased peak TNF activity by 2 units/ml and attenuated many of the physiological alterations due to sepsis. These results show that ibuprofen attenuates sepsis-induced injury and that alterations of acute septic insult are correlated with reduced plasma TNF activity in septic animals given ibuprofen.     

Ulinastatin protects rats from sepsis-induced acute lung injury by suppressing the JAK-STAT3 pathway

Sepsis is usually accompanied by pulmonary inflammations, leading to acute lung injury. During this process, endogenous factors that play a regulatory role could be exploited to therapeutically alleviate such lethal tissue injury. Here, we showed that ulinastatin (UTI) administration could reduce lung tissue necrosis and swelling during sepsis in rats. UTI treatment also decreased the levels of inflammatory mediators both in the lung and in the serum. Mechanistically, we showed that the phosphorylation levels of JAK2 and STAT3 in the lung of UTI-treated rats were lower than control rats and were correlated with the decreased levels of inflammatory mediators. Taken together, these results demonstrate the protective role of UTI in sepsis-induced acute lung injury.     

Knockdown of Burton’s tyrosine kinase confers potent protection against sepsis-induced acute lung injury

Sepsis is a common and critical complication in surgical patients that often leads to multiple organ failure syndrome (MOFS), including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Despite intensive supportive care and treatment modalities, the mortality of these patients remains high. In this study, we investigated the role of Burton’s tyrosine kinase (BTK), a member of the Btk/Tec family of cytoplasmic tyrosine kinases, in the pathogenesis of sepsis, and evaluated the protective effect of in vivo Btk RNA interference in a mouse model of cecal ligation and puncture (CLP)-induced sepsis. After intratracheal injection of Btk siRNA, the mice were then subjected to CLP to induce sepsis. The results demonstrated that this approach conferred potent protection against sepsis-induced ALI, as evidenced by a significant reduction in pathological scores, epithelial cell apoptosis, pulmonary edema, vascular permeability, and the expression of inflammatory cytokines and neutrophil infiltration in the lung tissues of septic mice. In addition, RNA interference of Btk significantly suppressed p-38 and iNOS signaling pathways in transduced alveolar macrophages in vitro. These results identify a novel role for BTK in lethal sepsis and provide a potential new therapeutic approach to sepsis and ALI.     

LL-37 and its analog FF/CAP18 attenuate neutrophil migration in sepsis-induced acute lung injury

Introduction: Sepsis can result in acute lung injury. LL-37 is a small cationic host defense peptide involved in anti-inflammatory. In the current study, it was hypothesized that antimicrobial peptide LL-37 could play a protective role in attenuating the progression of sepsis-induced acute lung injury. Methods: Forty male C57BL/6 mice were induced into sepsis using cecal ligation and puncture, and subsequently administered with recombinant mouse osteopontin. Peptides LL-37, the LL-37 analog (FF/CAP18, called sLL-37), or normal saline was intravenously administered into septic mice for 20 hours. Then, proinflammatory cytokines (IL-6 and IL-1β), acute lung injury markers (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and lactate dehydrogenase [LDH]), the neutrophil infiltration marker (myeloperoxidase [MPO]), and neutrophil infiltration were detected. Furthermore, the neutrophil migration and expression of migration-related factors (focal adhesion kinase [FAK], ERK, and P38) in differentiated HL-60 cells were detected. Results: Septic mice had upregulated IL-6, IL-1β, ALT, AST, LDH, MPO, p-FAK, p-ERK, and p-P38, infiltrated neutrophils, and migrated neutrophil-like HL-60 cells. In contrast, the administration of peptide LL-37 and sLL-37 inhibited all these changes. Compared with septic mice, it was found that proinflammatory cytokines, lung injury markers, MPO, and infiltrated neutrophils decreased in mice treated with LL-37 and sLL-37. In addition, the migrated neutrophil-like HL-60 cells and activated p-FAK, p-ERK, and p-P38 proteins were suppressed by LL-37 and sLL-37 treatments. Conclusions: Peptide LL-37 and its analog sLL-37 attenuated the progression of sepsis-induced acute lung injury by inhibiting neutrophil infiltration and migration through the FAK, ERK, and P38 pathways.     

Chitinase-like proteins are candidate biomarkers for sepsis-induced acute kidney injury

Sepsis-induced acute kidney injury (AKI) is a frequent complication of critically ill patients and leads to high mortality rates. The specificity of currently available urinary biomarkers for AKI in the context of sepsis is questioned. This study aimed to discover urinary biomarkers for septic AKI by contemporary shotgun proteomics in a mouse model for sepsis and to validate these in individual urine samples of mice and human septic patients with and without AKI. At 48 h after uterine ligation and inoculation of Escherichia coli, aged mice (48 weeks) became septic. A subgroup developed AKI, defined by serum creatinine, blood urea nitrogen, and renal histology. Separate pools of urine from septic mice with and without AKI mice were collected during 12 h before and between 36-48 h after infection, and their proteome compositions were quantitatively compared. Candidate biomarkers were validated by Western blot analysis of urine, plasma, and renal tissue homogenates from individual mice, and a limited number of urine samples from human septic patients with and without AKI. Urinary neutrophil gelatinase-associated lipocalin, thioredoxin, gelsolin, chitinase 3-like protein 1 and -3 (CHI3L3) and acidic mammalian chitinase were the most distinctive candidate biomarkers selected for septic AKI. Both neutrophil gelatinase-associated lipocalin and thioredoxin were detected in urine of septic mice and increased with severity of AKI. Acidic mammalian chitinase was only present in urine of septic mice with AKI. Both urinary chitinase 3-like protein 1 and -3 were only detected in septic mice with severe AKI. The human homologue chitinase 3-like protein 1 was found to be more excreted in urine from septic patients with AKI than without. In summary, urinary chitinase 3-like protein 1 and -3 and acidic mammalian chitinase discriminated sepsis from sepsis-induced AKI in mice. Further studies of human chitinase proteins are likely to lead to additional insights in septic AKI.     

Effects of ventilation on the surfactant system in sepsis-induced lung injury.

The present study examined the effects of mechanical ventilation, with or without positive end-expiratory pressure (PEEP), on the alveolar surfactant system in an animal model of sepsis-induced lung injury. Septic animals ventilated without PEEP had a significant deterioration in oxygenation compared with preventilated values (arterial PO(2)/inspired O(2) fraction 316 +/- 16 vs. 151 +/- 14 Torr; P < 0.05). This was associated with a significantly lower percentage of the functional large aggregates (59 +/- 3 vs. 72 +/- 4%) along with a significantly reduced function (minimum surface tension 17.7 +/- 1.8 vs. 11.8 +/- 3.8 mN/m) compared with nonventilated septic animals (P < 0.05). Sham animals similarly ventilated without PEEP maintained oxygenation, percent large aggregates and surfactant function. With the addition of PEEP, the deterioration in oxygenation was not observed in the septic animals and was associated with no alterations in the surfactant system. We conclude that animals with sepsis-induced lung injury are more susceptible to the harmful effects of mechanical ventilation, specifically lung collapse and reopening, and that alterations in alveolar surfactant may contribute to the development of lung dysfunction.     

复方清下汤对脓毒症大鼠肺组织ICAM-1及AQP-1基因表达的影响

目的探讨复方清下汤对脓毒症大鼠肺组织ICAM-1及AQP-1基因表达的影响,进一步探讨其减轻肺损伤机制。方法将健康SD大鼠随机分为4组,每组10只：（1）假手术组（SHAM组）,SHAM组只翻动盲肠,不做其他处理;（2）脓毒症肺损伤组（模型组）,以盲肠结扎穿孔诱发ALI模型;（3）盲肠结扎穿孔＋复方清下汤组（造模后立即灌胃给药,造模后8 h再次灌胃1次,剂量：10 m l/kg）;（4）盲肠结扎穿孔＋头孢哌酮舒巴坦（舒普深）（造模后立即静脉注射1次,造模后8 h再次静脉注射1次,剂量：0.2 g/kg）造模24 h后收集标本。应用免疫组织化学和Western blotting法检测肺组织中AQP-1、ICAM-1的表达,RT-PCR检测肺组织上述蛋白mRNA表达。结果与SHAM组比较,模型组应用免疫组织化学及W estern-b lotting法检测ICAM-1的表达均显著升高（P〈0.01）,而AQP-1则表达明显降低（P〈0.01）;RT-PCR法检测mRNA转录水平与蛋白表达结果基本一致。抗生素及中药处理组与模型组比较,上述细胞因子ICAM-1的表达明显降低（P〈0.05）,而AQP-1表达上调（P〈0.01）,抗生素及中药处理组2组检测数据相近。结论脓毒症大鼠肺损伤时细胞因子ICAM-1过度表达而AQP-1蛋白表达下调可能是造成脓毒症肺损伤的重要原因;复方清下汤处理的动物模型肺损伤减轻的同时ICAM-1和AQP-1表达变化,提示它可能通过调控ICAM-1和AQP-1表达起作用。     

复方清下汤对脓毒症大鼠细胞因子调控及其肺损伤的作用

目的盲肠结扎穿孔导致大肠埃希菌腹膜炎进而建立脓毒症肺损伤大鼠模型,检测炎性反应时,细胞因子的调控变化,探讨肺水肿的形成机制。经复方清下汤处理后检测上述变化,以期为脓毒症肺损伤的防治提出可能的新途径。方法将健康SD大鼠随机分为4组,每组10只：假手术组（SHAM组）,只翻动盲肠,不做其他处理;脓毒症肺损伤组（模型组）,盲肠结扎穿孔诱发AL（急性肺损伤）I模型;盲肠结扎穿孔＋复方清下汤组（造模后立即灌胃给药,造模后8 h再次灌胃1次,剂量为10 m l/kg）;盲肠结扎穿孔＋头孢哌酮/舒巴坦组（抗生素舒普深）（造模后立即静脉注射1次,造模后8 h再次静脉注射1次,剂量为0.2 g/kg）造模24 h后收集标本。分别观察大鼠的一般状态,肺组织匀浆MPO的测定,留取下腔静脉血清进行TNF-α的测定。镜下观察肺组织病理形态学改变,测量肺湿/干比值的变化。结果与SHAM组比较,模型组MPO、TNF-α水平明显升高（P〈0.01）,肺间质和肺泡内水肿,伴大量红细胞渗出（出血）和纤维素沉积,肺泡间隔毛细血管内皮细胞高度肿胀。肺湿/干比值明显增加（P〈0.01）,抗生素及中药处理组与模型组比较,MPO、TNF-α水平明显降低（P〈0.01）,肺湿/干比值明显降低（P〈0.01）,肺组织镜下表现：中药处理组及抗生素组较模型组肺泡间隔变窄,毛细血管内皮细胞肿胀减轻,出血减轻,纤维素渗出明显减少。结论脓毒症大鼠肺损伤时细胞因子TNF-α过度表达,炎性介质的过度表达可能是造成脓毒症肺损伤的重要原因,而复方清下汤可以减轻脓毒症时的肺损伤和抑制TNF-α的表达,它们之间可能存在一定的联系。     

Sirtuin 6 overexpression relieves sepsis-induced acute kidney injury by promoting autophagy

Sirtuin 6 (SIRT6) has the function of regulating autophagy. The aim of this study was to investigate the mechanism through which SIRT6 relieved acute kidney injury (AKI) caused by sepsis. The AKI model was established with lipopolysaccharides (LPS) using mice. Hematoxylin-eosin (HE) staining and streptavidin-perosidase (SP) staining was used to observe kidney tissue and test SIRT6 and LC3B proteins in kidney. Enzyme-linked immunosorbent assay (ELISA) was performed to detected the tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations. Cell counting kit-8 (CCK-8) assay and flow cytometry were carried out to test the cell viability and apoptosis rate respectively. Protein and mRNA were determined by Western blot and quantitative real-time polymerase chain reaction (qRT-PCR). AKI induced by LPS had self-repairing ability. At 12 h after modeling, the expression levels of TNF-α, IL-6, SIRT6 and LC3B-II/LC3B-I were first significantly increased and were then significantly decreased at 48 h after modeling. LPS inhibited the growth of HK-2 cells and promoted the expressions of TNF-α, IL-6, SIRT6 and LC3B. Overexpression of SIRT6 down-regulated the secretion of TNF-α and IL-6 induced by LPS. SIRT6 overexpression inhibited apoptosis induced by LPS and promoted autophagy in HK-2 cells. Silencing of the SIRT6 gene not only promoted the secretion of TNF-α and IL-6 by HK-2 cells, but also promoted apoptosis and reduced autophagy. LPS up-regulated the expression of SIRT6 gene in HK-2 cells. Overexpression of the SIRT6 gene could inhibit apoptosis and induce autophagy, which might be involved in repairing kidney damage caused by LPS.     

Role of pulmonary microvascular endothelial cell apoptosis in murine sepsis-induced lung injury in vivo

Background

Sepsis remains a common and serious condition with significant morbidity and mortality due to multiple organ dysfunction, especially acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Sepsis-induced ALI is characterized by injury and dysfunction of the pulmonary microvasculature and pulmonary microvascular endothelial cells (PMVEC), resulting in enhanced pulmonary microvascular sequestration and pulmonary infiltration of polymorphonuclear leukocytes (PMN) as well as disruption of the normal alveolo-capillary permeability barrier with leak of albumin-rich edema fluid into pulmonary interstitium and alveoli. The role of PMVEC death and specifically apoptosis in septic pulmonary microvascular dysfunction in vivo has not been established.

Methods

In a murine cecal ligation/perforation (CLP) model of sepsis, we quantified and correlated time-dependent changes in pulmonary microvascular Evans blue (EB)-labeled albumin permeability with (1) PMVEC death (propidium iodide [PI]-staining) by both fluorescent intravital videomicroscopy (IVVM) and histology, and (2) PMVEC apoptosis using histologic fluorescent microscopic assessment of a panel of 3 markers: cell surface phosphatidylserine (detected by Annexin V binding), caspase activation (detected by FLIVO labeling), and DNA fragmentation (TUNEL labeling).

Results

Compared to sham mice, CLP-sepsis resulted in pulmonary microvascular barrier dysfunction, quantified by increased EB-albumin leak, and PMVEC death (PI+ staining) as early as 2 h and more marked by 4 h after CLP. Septic PMVEC also exhibited increased presence of all 3 markers of apoptosis (Annexin V+, FLIVO+, TUNEL+) as early as 30 mins – 1 h after CLP-sepsis, which all similarly increased markedly until 4 h. The time-dependent changes in septic pulmonary microvascular albumin-permeability barrier dysfunction were highly correlated with PMVEC death (PI+; r = 0.976, p < 0.01) and PMVEC apoptosis (FLIVO+; r = 0.991, p < 0.01). Treatment with the pan-caspase inhibitor Q-VD prior to CLP reduced PMVEC death/apoptosis and attenuated septic pulmonary microvascular dysfunction, including both albumin-permeability barrier dysfunction and pulmonary microvascular PMN sequestration (p < 0.05). Septic PMVEC apoptosis and pulmonary microvascular dysfunction were also abrogated following CLP-sepsis in mice deficient in iNOS (Nos2^−/−) or NADPH oxidase (p47^phox−/− or gp91^phox−/−) and in wild-type mice treated with the NADPH oxidase inhibitor, apocynin.

Conclusions

Septic murine pulmonary microvascular dysfunction in vivo is due to PMVEC death, which is mediated through caspase-dependent apoptosis and iNOS/NADPH-oxidase dependent signaling.     

Immature lung and acute lung injury

Acute lung injury occurs mostly in the very low birth weight and extremely low birth weight infants. The pathological process leading to acute lung injury includes immature and/or diseased lung that experienced oxidative stress, inflammation and mechanical insult with the bronchial, alveolar and capillary injuries and cell death. It may be the first step to the subsequent development of chronic lung disease of prematurity or bronchopulmonary dysplasia. The mechanisms of lung injury are extensively investigated in the experimental models and clinical studies, mostly performed on the adult patients. At present, the explanations of the mechanism(s) leading to lung tissue injury in tiny premature babies are just derived from these studies. Acute lung injury seems to be rather a syndrome than a well-defined nosological unit and is of multifactorial etiology. The purpose of this review is to discuss the main factors contributing to the development of acute lung injury in the very low or extremely low birth weight infants--lung immaturity, mechanical injury, oxidative stress and inflammation. Nevertheless, numerous other factors may influence the status of immature lung after delivery.     

Olaparib attenuates sepsis-induced acute multiple organ injury via ERK-mediated CD14 expression

Sepsis is characterized by persistent systemic inflammation, which can cause multi-organ dysfunction. The poly polymerase-1 inhibitor olaparib possesses anti-inflammatory properties. This study aimed to assess the effects of olaparib (pre- and post-treatments) on sepsis, and to investigate whether it could suppress CD14 expression via the ERK pathway in polymicrobial sepsis and peritoneal macrophages models. Sepsis was induced by cecal ligation and puncture in C57BL/6 male mice. Fifty mice were randomly divided into five groups: The sham group was treated with vehicle or olaparib, the cecal ligation and puncture group with vehicle or with olaparib (5 mg/kg i.p.) 1 h before or 2 h after surgery. Olaparib pretreatment significantly improved the survival of septic mice (P < 0.001). Pre- and post-treatment of mice with olaparib partly alleviated cecal ligation and puncture-induced organ injury by decreasing the amounts of the pro-inflammatory mediators TNF-α and IL-6 as well as bacterial burden in the serum, peritoneal lavage fluid, and organs (P < 0.05). The protective effect of olaparib was associated with CD14 suppression via inhibition of ERK activation. Olaparib facilitated negative regulation of ERK-mediated CD14 expression, which may contribute to multi-organ injury in sepsis.     

BIG1 mediates sepsis-induced lung injury by modulating lipid raft-dependent macrophage inflammatory responses

Sepsis is a systemic inflammatory response syndrome with high mortality.It has been reported that brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BI...     

Gamma-enolase predicts lung damage in severe acute pancreatitis-induced acute lung injury

Severe acute pancreatitis (SAP) associated acute lung injury (ALI) accounts for about 70% mortality of SAP patients. However, there are no precise biomarkers for the disease currently. Herein, we evaluated the potential of gamma-enolase (ENO2), against its universal isoform alpha-enolase (ENO1), as a marker of SAP–ALI in a rat model. Firstly, 16 male Sprague–Dawley rats were randomly divided into two groups, Sham (n?=?8) and SAP–ALI (n?=?8), for pancreatitis induction. Ultra-structure examination by electron microscopy and HE staining were used for lung injury assessment. Lung tissue expressions of alpha-enolase and gamma-enolase were evaluated by qRT-PCR and immunohistochemistry. In a prospective validation experiment, 28 rats were used: sham (n?=?8), SAP–ALI at 3 h (3 h, n?=?10), and SAP–ALI at 24 h (24 h, n?=?10). Lung tissue damage, tissue expression and circulating alpha-enolase and gamma-enolase levels were evaluated. Elevated serum levels of α-amylase and TNF-α were observed in SAP rats but not in sham-operated rats. Histological examination of pancreatic and lung tissues indicated marked damage in SAP rats. While alpha-enolase was universally expressed, gamma-enolase was expressed only in damaged lung tissues. Gamma-enolase was detected in lung tissues, BALF, and serum as early as 3 h post-surgery when physical pathological damage was not apparent. Unlike alpha-enolase, secreted and/or circulating gamma-enolase level progressively increased, especially in serum, as lung damage progressed. Thus, gamma-enolase may signal and correlate lung tissue damage well before obvious physical pathological tissue damage and might be a candidate diagnostic and/or prognostic marker.     

Effects of continuous erythropoietin receptor activator in sepsis-induced acute kidney injury and multi-organ dysfunction

Background

Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI.

Methods

Rats were randomized into three groups: control; CLP; and CLP+CERA (5 µg/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting—to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-κB)—and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1β, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection.

Results

Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-κB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats.

Conclusion

CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.     

Monokine-induced acute lung injury in rabbits

Interleukin-1 (IL-1) mediates components of the acute phase response, stimulates granulocyte metabolism, and induces endothelial cell surface changes. We studied in unanesthetized rabbits the effects of intravenous divided dose infusions of a murine monokine preparation containing IL-1 activity, on circulating granulocytes, their sequestration within the pulmonary microvasculature, pulmonary edema formation, and changes in pulmonary vascular permeability. Monokine administration induced significant (P less than 0.01) granulocytopenia as well as a significant (P less than 0.001) increase in mean alveolar septal wall granulocytes per high power field (HPF) compared with saline-injected controls. Infusions of the monokine preparation significantly (P less than 0.005) increased lung wet-to-dry weight ratios as well as significantly (P less than 0.025) increased pulmonary extravasation of radiolabeled albumin. Electron microscopic analysis of lung sections obtained from monokine-infused animals demonstrated endothelial injury, perivascular edema, and extravasation of an ultrastructural tracer. We conclude that a monokine preparation containing IL-1 activity can induce profound granulocytopenia, pulmonary leukostasis, and acute pulmonary vascular endothelial injury.     

Cytokine-mediated inflammation in acute lung injury

Clinical acute lung injury (ALI) is a major cause of acute respiratory failure in critically ill patients. There is considerable experimental and clinical evidence that pro- and anti-inflammatory cytokines play a major role in the pathogenesis of inflammatory-induced lung injury from sepsis, pneumonia, aspiration, and shock. A recent multi-center clinical trial found that a lung-protective ventilatory strategy reduces mortality by 22% in patients with ALI. Interestingly, this protective ventilatory strategy was associated with a marked reduction in the number of neutrophils and the concentration of pro-inflammatory cytokines released into the airspaces of the injured lung. Further research is needed to establish the contribution of cytokines to both the pathogenesis and resolution of ALI.