Mechanisms of enhanced lung injury during sepsis

A major complication in sepsis is progressively impaired lung function and susceptibility to intrapulmonary infection. Why sepsis predisposes the lung to injury is not clear. In the current studies, rats were rendered septic by cecal ligation/puncture and evaluated for increased susceptibility to injury after a direct pulmonary insult (deposition of IgG immune complexes or airway instillation of lipopolysaccharide). By itself, cecal ligation/puncture did not produce evidence of lung injury. However, after a direct pulmonary insult, lung injury in septic animals was significantly enhanced. Enhanced lung injury was associated with increased accumulation of neutrophils in lung, enhanced production of CXC chemokines (but not tumor necrosis factor-alpha) in bronchoalveolar lavage fluids, and increased expression of lung vascular intercellular adhesion molecule-1 (ICAM-1). Complement depletion or treatment with anti-C5a abolished all evidence of enhanced lung injury in septic animals. When stimulated in vitro, bronchoalveolar lavage macrophages from septic animals had greatly enhanced CXC chemokine responses as compared with macrophages from sham-operated animals or from septic animals that had been complement depleted. These data indicate that the septic state causes priming of lung macrophages and suggest that enhanced lung injury in the septic state is complement dependent and related to increased production of CXC chemokines.     

Role of oxidants in microbial pathophysiology.

Reactive oxidant species (superoxide, hydrogen peroxide, hydroxyl radical, hypohalous acid, and nitric oxide) are involved in many of the complex interactions between the invading microorganism and its host. Regardless of the source of these compounds or whether they are produced under normal conditions or those of oxidative stress, these oxidants exhibit a broad range of toxic effects to biomolecules that are essential for cell survival. Production of these oxidants by microorganisms enables them to have a survival advantage in their environment. Host oxidant production, especially by phagocytes, is a counteractive mechanism aimed at microbial killing. However, this mechanism may be contribute to a deleterious consequence of oxidant exposure, i.e., inflammatory tissue injury. Both the host and the microorganism have evolved complex adaptive mechanisms to deflect oxidant-mediated damage, including enzymatic and nonenzymatic oxidant-scavenging systems. This review discusses the formation of reactive oxidant species in vivo and how they mediate many of the processes involved in the complex interplay between microbial invasion and host defense.     

Mechanisms of acute inflammatory lung injury induced by abdominal sepsis

Sequestration of neutrophils and release of histotoxic mediators are considered important for the development of pathologic alterations of the lung defined as adult respiratory distress syndrome. Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease. In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus. In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-gamma, but independent of tumor necrosis factor (TNF). Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1. Expression of MIP-2, KC, MIP-1alpha and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery. Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.     

Role of chorioamnionitis in the development of sepsis during labor

The authors emphasize the importance of pyoseptic diseases of the reproductive system, which are a major cause of maternal mortality. Clinical and morphological criteria have been elaborated to diagnose a special form of obstetric sepsis during labor. The inflammatory infiltrate was investigated by immunohistochemical studies using monoclonal antibodies and tumor necrosis factor. Lesions of the fetal integument and placenta have been found to be an initiating factor. The fetal integuments with signs of chorioamnionitis serve as the entry of pathogens during the septic process, promoted the development and course of septicemia during labor and complications, such as disseminated intravascular coagulation and infectious-toxic shock.     

Role of airway recruitment and derecruitment in lung injury

The mechanical forces generated during the ventilation of patients with acute lung injury causes significant lung damage and inflammation. Low-volume ventilation protocols are commonly used to prevent stretch-related injury that occurs at high lung volumes. However, the cyclic closure and reopening of pulmonary airways at low lung volumes, i.e., derecruitment and recruitment, also causes significant lung damage and inflammation. In this review, we provide an overview of how biomedical engineering techniques are being used to elucidate the complex physiological and biomechanical mechanisms responsible for cellular injury during recruitment/derecruitment. We focus on the development of multiscale, multiphysics computational models of cell deformation and injury during airway reopening. These models, and the corresponding in vitro experiments, have been used to both elucidate the basic mechanisms responsible for recruitment/derecruitment injury and to develop alternative therapies that make the epithelium more resistant to injury. For example, models and experiments indicate that fluidization of the cytoskeleton is cytoprotective and that changes in cytoskeletal structure and cell mechanics can be used to mitigate the mechanotransduction of oscillatory pressure into inflammatory signaling. The continued application of biomedical engineering techniques to the problem of recruitment/derecruitment injury may therefore lead to novel and more effective therapies.     

Pretreatment with anti-flagellin serum delays acute lung injury in rats with sepsis

Objective

This study examined the reduction of sepsis-induced ALI by inhibition of flagellin-stimulated TLR5 signaling.

Methods

Rats were randomly divided into three groups: one group served as the sham-operated group (control group), and the other two groups received the induction of sepsis (sepsis and treatment groups). The treatment group was injected with anti-flagellin serum before induction of sepsis. At 2, 4, 6, 12, 24, and 48?h following induction of sepsis (six time-point subgroups, n?=?10 per subgroup), arterial PaO₂, wet/dry (W/D) lung weight ratios, levels of serum and BALF flagellin and TNF-α, pulmonary pathological alterations, and TLR5 mRNA expression in the lungs were examined.

Results

Compared to sham-operated rats, septic rats had: increased levels of serum and BALF flagellin at 6, 12, 24, and 48?h; reduced arterial PaO₂; elevated W/D lung weight ratio; increased serum and BALF TNF-α levels; and up-regulated TLR5 mRNA expression at 12, 24, and 48?h (P?2, increased W/D lung weight ratios, elevated serum and BALF TNF-α levels, and up-regulated TLR5 mRNA expression at 24 and 48?h (P?Conclusion Neutralizing the actions of circulating flagellin with anti-flagellin serum delayed the development of ALI in rats with sepsis.     

Role of oxidants in the signaling pathway of preconditioning

This review focuses on the possible role of reactive oxygen species in the pathogenesis of this phenomenon. Evidence in support of a role of oxidants in preconditioning has come from the observation that administration of oxygen radical scavengers during the reperfusion period following the initial "preconditioning" ischemia could prevent the phenomenon. In addition, a brief exposure to a low, nontoxic dose of oxygen radicals may reproduce the beneficial effects of ischemic preconditioning, thus suggesting that radicals can directly trigger the preconditioning pathway. To explain the effects of oxidants in this setting, it has been suggested that reperfusion after the initial, "preconditioning" ischemic episode results in the generation of relatively low amounts of oxygen radicals, which are insufficient to determine cell necrosis, but nevertheless could modify cellular activities that have been implicated as mediators of the preconditioning phenomenon. Recent evidence suggests that low levels of oxidants may have a modulatory role on several cell functions. Possible mechanisms of oxidant-mediated protection might be protein kinase C and other kinases, ATP-dependent potassium channels, or changes in sulfhydryl group redox state, while an effect on adenosine metabolism, or the induction of myocardial stunning presumably does not contribute to oxidant-mediated preconditioning. Finally, de novo protein synthesis and gene expression, and increased antioxidant defenses might be involved in the late phase of preconditioning. In summary, available data strongly suggest that oxygen radicals might be possible mediators of preconditioning. However, further investigation is required to clearly elucidate their exact role and mechanisms of action.     

Role of chemokines in the pathogenesis of acute lung injury

Acute lung injury (ALI) is due to an uncontrolled systemic inflammatory response resulting from direct injury to the lung or indirect injury in the setting of a systemic process. Such insults lead to the systemic inflammatory response syndrome (SIRS), which includes activation of leukocytes-alveolar macrophages and sequestered neutrophils-in the lung. Although systemic inflammatory response syndrome is a physiologic response to an insult, systemic leukocyte activation, if excessive, can lead to end organ injury, such as ALI. Excessive recruitment of leukocytes is critical to the pathogenesis of ALI, and the magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ALI. Leukocyte recruitment is a well orchestrated process that depends on the function of chemokines and their receptors. Understanding the mechanisms that contribute to leukocyte recruitment in ALI may ultimately lead to the development of effective therapeutic strategies.     

Type 2 deiodinase and host responses of sepsis and acute lung injury

The role of thyroid hormone metabolism in clinical outcomes of the critically ill remains unclear. Using preclinical models of acute lung injury (ALI), we assessed the gene and protein expression of type 2 deiodinase (DIO2), a key driver for synthesis of biologically active triiodothyronine, and addressed potential association of DIO2 genetic variants with ALI in a multiethnic cohort. DIO2 gene and protein expression levels in murine lung were validated by microarrays and immunoblotting. Lung injury was assessed by levels of bronchoalveolar lavage protein and leukocytes. Single-nucleotide polymorphisms were genotyped and ALI susceptibility association assessed. Significant increases in both DIO2 gene and D2 protein expression were observed in lung tissues from murine ALI models (LPS- and ventilator-induced lung injury), with expression directly increasing with the extent of lung injury. Mice with reduced levels of DIO2 expression (by silencing RNA) demonstrated reduced thyroxine levels in plasma and increased lung injury (increased bronchoalveolar lavage protein and leukocytes), suggesting a protective role for DIO2 in ALI. The G (Ala) allele of the Thr92Ala coding single-nucleotide polymorphism (rs225014) was protective in severe sepsis and severe sepsis-associated ALI after adjustments for age, sex, and genetic ancestry in a logistic regression model in European Americans. Our studies indicate that DIO2 is a novel ALI candidate gene, the nonsynonymous Thr92Ala coding variant of which confers ALI protection. Increased DIO2 expression may dampen the ALI inflammatory response, thereby strengthening the premise that thyroid hormone metabolism is intimately linked to the integrated response to inflammatory injury in critically ill patients.     

白细胞在油酸引起的急性肺损伤中的作用

以0.1ml/kg油酸静脉注入复制大鼠急性肺损伤模型。实验动物出现呼吸困难、低氧血症和白细胞减少。注油酸二小时后,肺指数、血清及BALF中β-葡萄糖醛酸酶(β-g)活力明显增高。组织学检查可看到肺微血管内有白细胞聚集,间质有白细胞浸润,间质和肺泡内水肿,出血和充血。以抗多形核白细胞抗体造成白细胞减少的大鼠,肺损伤就没有正常大鼠那样严重。结果表明白细胞参与油酸引起的急性肺损伤。     

凝血和纤溶失衡在急性肺损伤中的作用

急性肺损伤(acute lung injury,ALI),以肺泡上皮细胞和血管内皮屏障损伤、急性炎症反应、富含蛋白的肺水肿为特征,是一种临床常见的危重病症,可进一步发展为急性呼吸窘迫综合症(acute respiratory distress syndrome,ARDS).     

Role of alveolar macrophages in Candida-induced acute lung injury.

Recent studies have shown that alveolar macrophages (AMs) not only act as phagocytes but also play a central role as potent secretory cells in various lung diseases, including pneumonia and acute respiratory distress syndrome. The behavior of AMs during disseminated candidiasis, however, is insufficiently elucidated. This study is the first to report disseminated candidiasis in AM-depleted mice and to analyze the effect of AMs on Candida-induced acute lung injury. While all AM-sufficient mice died by day 2 after infection with Candida albicans, no mortality was observed among AM-depleted mice. Unexpectedly, the CFU numbers of C. albicans isolated from the lungs of AM-depleted mice were significantly higher than those for C. albicans isolated from AM-sufficient mice. The lung wet-to-dry weight ratio was lower for AM-depleted mice than for AM-sufficient mice, although this difference was not significant. We found that bronchoalveolar lavage fluid (BALF) from AM-depleted mice in candidemia contained fewer neutrophils than BALF from AM-sufficient mice. In addition, myeloperoxidase activities in lung homogenates of AM-depleted mice were significantly lower than those in homogenates of AM-sufficient mice. A significant decrease in levels of murine macrophage inflammatory protein 2 (MIP-2), a potent chemoattractant for neutrophils, was noted in lung homogenates from AM-depleted mice compared with levels in homogenates from AM-sufficient mice. Immunohistochemical studies using anti-MIP-2 antibodies revealed that AMs were the cellular source of MIP-2 within the lung during candidemia. We observed that AM depletion decreased levels of AM-derived neutrophil chemoattractant, alleviated acute lung injury during candidemia, and prolonged the survival of mice in candidemia, even though clearance of C. albicans from the lungs was reduced.     

Role of microRNAs in sepsis

Introduction

MicroRNAs have been found to be of high significance in the regulation of various genes and processes in the body. Sepsis is a serious clinical problem which arises due to the excessive host inflammatory response to infection. The non-specific clinical features and delayed diagnosis of sepsis has been a matter of concern for long time.

Findings

MicroRNAs could enable better diagnosis of sepsis and help in the identification of the various stages of sepsis. Improved diagnosis may enable quicker and more effective treatment measures. The initial acute and transient phase of sepsis involves excessive secretion of pro-inflammatory cytokines which causes severe damage. MicroRNAs negatively regulate the toll-like receptor signaling pathway and regulate the production of inflammatory cytokines during sepsis. Likewise, microRNAs have shown to regulate the vascular barrier and endothelial function in sepsis. They are also involved in the regulation of the apoptosis, immunosuppression, and organ dysfunction in later stages of sepsis. Their importance at various levels of the pathophysiology of sepsis has been discussed along with the challenges and future perspectives.

Conclusion

MicroRNAs could be key players in the diagnosis and staging of sepsis. Their regulation at various stages of sepsis suggests that they may have an important role in altering the outcome associated with sepsis.

     

Neurokinin-1 receptor antagonist treatment protects mice against lung injury in polymicrobial sepsis

Earlier work from our laboratory has suggested a role for the neuropeptide substance P (SP) in inducing lung injury in sepsis. In that study, mice lacking the preprotachykinin-A gene, which encodes for SP, were protected against lung injury in sepsis. To further substantiate the role of SP in sepsis and to study its mechanism, we have evaluated the effect of SR140333, a SP receptor antagonist, on lung injury in sepsis, which was induced in male Swiss mice by cecal ligation and puncture (CLP). Sham-operated animals received the same surgical procedure, except CLP. Vehicle or SR140333 (1 mg/kg, s.c.) was administered to CLP mice 30 min before or 1 h after the CLP. Eight hours after surgery, lung tissue was collected and analyzed for myeloperoxidase (MPO) activity, chemokines, cytokines, and adhesion molecules. The CLP procedure alone caused a significant increase in the lung levels of MIP-2, MCP-1, IL-1beta, IL-6, ICAM-1, E- and P-selectin, and MPO activity when compared with sham-operated mice. SR140333 injected 30 min before or 1 h after CLP significantly attenuated the increased lung MPO activity and levels of MIP-2, MCP-1, IL-1beta, IL-6, ICAM-1, and E- and P-selectin compared with CLP-operated mice injected with the vehicle. Histological evaluation of the lung sections further supported the beneficial effect of SR140333 on lung inflammation. Therefore, SP receptor antagonism can be a potential therapeutic target in polymicrobial sepsis, and this effect is brought about via reduction in leukocyte recruitment.     

选择素在家兔糖尿病酮症酸中毒肺损伤中的作用

目的:研究选择素在糖尿病酮症酸中毒肺损伤中的作用。方法:雄性新西兰家兔12只,随机分为实验组(DK组)₆只和生理盐水对照组(NS组)₆只,DK组给予四氧嘧啶(alloxan)₁₅₀mg·kg^-1和链脲佐菌素(STZ)₁₅₀mg·kg^-1,对照组给予等剂量生理盐水,72h后处死动物,检测动脉血气,取肺组织进行组化研究。结果:实验组动物免疫组化显示选择素的表达增多。结论:糖尿病酮症酸中毒肺损伤时选择素起重要作用.     

细胞因子风暴在2019新型冠状病毒肺炎肺损伤中的作用

2019新型冠状病毒肺炎(coronavirus disease 2019,COVID-19)是一种以肺为主要靶器官的全身多器官损伤性疾病.细胞因子风暴在COVID-19患者肺损伤中发挥重要作用,严重急性呼吸窘迫综合征冠状病毒-2靶向血管紧张素转换酶2(angiotensin-converting enzyme 2,A...     

外周血Th17细胞对脓毒症急性肺损伤病情严重程度及预后的评估价值

观察脓毒症急性肺损伤患者外周血Th17细胞水平与病情严重程度及预后的关系,探讨其在脓毒症急性肺损伤发生发展中的临床作用。以190例脓毒症患者为研究对象,按临床表现分为脓毒症普通组(110例)和脓毒症肺损伤组(80例)。根据脓毒症肺损伤患者病情严重程度将其分为低危组(29例)、中危组(28例)和高危组(23例);按脓毒症肺损伤患者临床结局将其分为存活组(64例)和死亡组(16例)。采用流式细胞仪检测各组外周血Th17细胞比例,同时记录急性生理学与慢性健康状况(APACHE Ⅱ)评分情况,分别比较各组外周血Th17细胞比例及APACHE Ⅱ评分水平的差异以及Th17细胞水平与APACHE Ⅱ评分的相关性,评价外周血Th17细胞水平对脓毒症肺损伤患者病情严重程度与临床预后的评估价值。结果显示脓毒症肺损伤组患者外周血Th17细胞及IL-17水平明显高于脓毒症普通组患者(P0.05);低危组、中危组及高危组间外周血Th17细胞水平、IL-17及APACHE Ⅱ评分的差异具有统计学意义(P0.05),其中,高危组外周血Th17细胞水平、IL-17及APACHE Ⅱ评分最高,中危组次之,低危组最低(P0.05);死亡组外周血Th17细胞水平、IL-17及APACHE Ⅱ评分显著高于存活组(P0.05)。相关性分析显示,血清外周血Th17细胞水平与APACHE Ⅱ评分(r=0.81,P=0.00)及死亡率(r=0.43,P=0.00)呈正相关。ROC曲线分析显示,外周血Th17细胞水平曲线下面积(ACU)为0.842(95%CI:0.784~0.908),其最佳工作点为7.0%,此时判断脓毒症肺损伤患者预后不良的敏感度和特异度分别为81.83%和86.82%。研究表明脓毒症急性肺损伤患者外周血Th17细胞水平的增加与其病情严重程度及预后密切相关,其可作为一项有效的预测指标,具有一定的临床应用价值。