Bupleurum chinense DC polysaccharides attenuates lipopolysaccharide-induced acute lung injury in mice

Bupleurum chinense DC had hepato-protective, anti-inflammatory, antipyretic, analgesic, and immunomodulatory effect in traditional Chinese medicine. This study was to determine whether the crude polysaccharides isolated from the roots of Bupleurum chinense DC (BCPs) attenuated lipopolysaccharide (LPS)-induced acute lung injury in mice. Mice were challenged with LPS intratracheally 2 h before BCPs (20, 40 and 80 mg/kg) administration. The bronchoalveolar lavage fluid (BALF) was collected 24 h after LPS challenge. Treatment with BCPs reduced lung wet-to-dry weight ratio. The elevated number of total cells and protein concentration in BALF was reduced. The increased level of myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α) in BALF, and serum nitric oxide (NO) were also inhibited. BCPs significantly attenuated lung injury with improved lung morphology and reduced complement deposition. These results suggested that the effect of BCPs against ALI might be related with its inhibitory effect on excessive activation of complement and on the production of proinflammatory mediators.     

1α,25-Dihydroxyvitamin D₃ inhibits neutrophil recruitment in hamster model of acute lung injury

The chemokine interleukin-8 (IL-8) is involved in the pathogenesis of acute lung injury (ALI). Although several studies have reported that 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃) suppresses IL-8 production in vitro and in vivo, 1α,25(OH)₂D₃ has not been demonstrated to be effective in an animal model of ALI. Here, we determined its effects of 1α,25(OH)₂D₃ in a hamster model where ALI was induced by lipopolysaccharide (LPS) inhalation. 1α,25(OH)₂D₃ inhibited neutrophil recruitment in the lung by approximately 40% without increasing plasma calcium concentration, while it did not inhibit monocyte recruitment. Our findings show that vitamin D₃ analogues may be suitable as novel anti-inflammatory agents for ALI.     

The lactoperoxidase system links anion transport to host defense in cystic fibrosis

Chronic respiratory infections in cystic fibrosis result from CFTR channel mutations but how these impair antibacterial defense is less clear. Airway host defense depends on lactoperoxidase (LPO) that requires thiocyanate (SCN-) to function and epithelia use CFTR to concentrate SCN- at the apical surface. To test whether CFTR mutations result in impaired LPO-mediated host defense, CF epithelial SCN- transport was measured. CF epithelia had significantly lower transport rates and did not accumulate SCN- in the apical compartment. The lower CF [SCN-] did not support LPO antibacterial activity. Modeling of airway LPO activity suggested that reduced transport impairs LPO-mediated defense and cannot be compensated by LPO or H2O2 upregulation.     

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.     

Tannic acid protects against experimental acute lung injury through downregulation of TLR4 and MAPK

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) remain a major cause of morbidity and mortality in critically ill patients, and no specific therapies are still available to control the mortality rate. Thus, we explored the preventive and therapeutic effects of tannic acid (TA), a natural polyphenol in the context of ALI. We used in vivo and in vitro models, respectively, using lipopolysaccharide (LPS) to induce ALI in mice and exposing J774 and BEAS-2B cells to LPS. In both preventive and therapeutic approaches, TA attenuated LPS-induced histopathological alterations, lipid peroxidation, lung permeability, infiltration of inflammatory cells, and the expression of proinflammatory mediators. In addition, in-vitro study showed that TA treatment could reduce the expression of proinflammatory mediators. Further studies revealed that TA-dampened inflammatory responses by downregulating the LPS-induced toll-like receptor 4 (TLR4) expression and inhibiting extracellular-signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) activation. Furthermore, cells treated with the inhibitors of ERK1/2 (PD98059) and p38 (SB203580) mitigated the expression of cytokines induced by LPS, thus suggesting that ERK1/2 and p38 activity are required for the inflammatory response. In conclusion, TA could attenuate LPS-induced inflammation and may be a potential therapeutic agent for ALI-associated inflammation in clinical settings.     

Interactions between PBEF and oxidative stress proteins--a potential new mechanism underlying PBEF in the pathogenesis of acute lung injury

Identification of pre-B-cell colony-enhancing factor (PBEF) interacting partners may reveal new molecular mechanisms of PBEF in the pathogenesis of acute lung injury (ALI). The interactions between PBEF and NADH dehydrogenase subunit 1(ND1), ferritin light chain and interferon induced transmembrane 3 (IFITM3) in human pulmonary vascular endothelial cells were identified and validated. ND1, ferritin and IFITM3 are involved in oxidative stress and inflammation. Overexpression of PBEF increased its interactions and intracellular oxidative stress, which can be attenuated by rotenone. The interaction modeling between PBEF and ND1 is consistent with the corresponding experimental finding. These interactions may underlie a novel role of PBEF in the pathogenesis of ALI.     

不同浓度hUCMSCs对重度烧伤大鼠急性肺损伤的保护作用初探

目的:通过气管内给药的方法比较不同浓度人脐带间充质干细胞气管内移植对重度烧伤致急性肺损伤大鼠的保护作用。方法:建立50%面积全层烫伤大鼠模型,将75只成熟雄性Wistar大鼠随机分为正常对照组(A组)、生理盐水组(B组)、1×10~5HUCMSCs移植组(C)、5×10~5HUCMSCs移植组(D)、1×10~6HUCMSCs移植组(E),每组15只,B组及移植组(C、D、E组)烫伤后立即液体复苏,B组烫伤后气管内滴注0.2 m L生理盐水,移植组气管内滴注不同浓度h UCMSCs,分别在移植后的天第1、3、7天留取大鼠肺组织标本,HE染色观察肺组织病理变化,MPO、CD68免疫组化染色观察肺组织中性粒细胞及肺巨噬细胞阳性表达情况。结果:肺组织病理切片可见:A组各时间点肺泡腔清晰,肺泡结构完整,偶见少量炎性细胞。烫伤后第1天,B组及移植组(C、D、E组)肺泡间隔增厚,大量红细胞漏出及炎性细胞浸润。烫伤后第3天,各组肺泡结构较前清晰,炎性细胞浸润及红细胞漏出较第一天减少,与B组相比移植组肺泡结构清晰,间隔变薄,移植组各组间改变不明显。烫伤后第7天,移植组肺组织损伤较B组明显减轻,E组损伤肺组织恢复最为明显。MPO染色显示:与A组相比,阳性细胞数在烫伤后第1天明显增加(P0.05),但各组之间无明显差异。在烫伤后第3天,与B组相比,移植组阳性细胞数减少明显(P0.05),E组阳性细胞减少明显(P0.05);在烫伤后第7天E组阳性细胞数量较其他组显著减少(P0.05)。CD68染色显示在烫伤后第1天各组阳性细胞显著增多(P0.05),在烫伤后第3天移植组阳性细胞数减少(P0.05),但各移植组间无明显差异,烫伤后第7天移植组阳性细胞数量较B组明显减少(P0.05),E组较C、D组阳性细胞减少有显著差异(P0.05)。结论:气管内移植HUCMSCs能修复重度烧伤后损伤的肺组织,减少肺组织中性粒细胞及巨噬细胞的浸润,且1×10~6HUCMSCs移植效果更明显。     

Downregulated microRNA-27b attenuates lipopolysaccharide-induced acute lung injury via activation of NF-E2-related factor 2 and inhibition of nuclear factor κB signaling pathway

Acute lung injury (ALI) is a life-threatening, diffuse heterogeneous lung injury characterized by acute onset, pulmonary edema, and respiratory failure. Lipopolysaccharide (LPS) is a leading cause for ALI and when administered to a mouse it induces a lung phenotype exhibiting some of the clinical characteristics of human ALI. This study focused on investigating whether microRNA-27b (miR-27b) affects ALI in a mouse model established by LPS-induction and to further explore the underlying mechanism. After model establishment, the mice were treated with miR-27b agomir, miR-27b antagomir, or D-ribofuranosylbenzimidazole (an inhibitor of nuclear factor-E2-related factor 2 [Nrf2]) to determine levels of miR-27b, Nrf2, nuclear factor kappa-light-chain-enhancer of activated B cells nuclear factor κB (NF-κB), p-NF-κB, and heme oxygenase-1 (HO-1). The levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF) were determined. The results of luciferase activity suggested that Nrf2 was a target gene of miR-27b. It was indicated that the Nrf2 level decreased in lung tissues from ALI mice. The downregulation of miR-27b decreased the levels of IL-1β, IL-6, and TNF-α in BALF of ALI mice. Downregulated miR-27b increased Nrf2 level, thus enhancing HO-1 level along with reduction of NF-κB level as well as the extent of NF-κB phosphorylation in the lung tissues of the transfected mice. Pathological changes were ameliorated in LPS-reduced mice elicited by miR-27b inhibition. The results of this study demonstrate that downregulated miR-27b couldenhance Nrf2 and HO-1 expressions, inhibit NF-κB signaling pathway, which exerts a protective effect on LPS-induced ALI in mice.     

Mechanical Stretch Inhibits Lipopolysaccharide-induced Keratinocyte-derived Chemokine and Tissue Factor Expression While Increasing Procoagulant Activity in Murine Lung Epithelial Cells

Previous studies have shown that the innate immune stimulant LPS augments mechanical ventilation-induced pulmonary coagulation and inflammation. Whether these effects are mediated by alveolar epithelial cells is unclear. The alveolar epithelium is a key regulator of the innate immune reaction to pathogens and can modulate both intra-alveolar inflammation and coagulation through up-regulation of proinflammatory cytokines and tissue factor (TF), the principal initiator of the extrinsic coagulation pathway. We hypothesized that cyclic mechanical stretch (MS) potentiates LPS-mediated alveolar epithelial cell (MLE-12) expression of the chemokine keratinocyte-derived cytokine (KC) and TF. Contrary to our hypothesis, MS significantly decreased LPS-induced KC and TF mRNA and protein expression. Investigation into potential mechanisms showed that stretch significantly reduced LPS-induced surface expression of TLR4 that was not a result of increased degradation. Decreased cell surface TLR4 expression was concomitant with reduced LPS-mediated NF-κB activation. Immunofluorescence staining showed that cyclic MS markedly altered LPS-induced organization of actin filaments. In contrast to expression, MS significantly increased LPS-induced cell surface TF activity independent of calcium signaling. These findings suggest that cyclic MS of lung epithelial cells down-regulates LPS-mediated inflammatory and procoagulant expression by modulating actin organization and reducing cell surface TLR4 expression and signaling. However, because LPS-induced surface TF activity was enhanced by stretch, these data demonstrate differential pathways regulating TF expression and activity. Ultimately, loss of LPS responsiveness in the epithelium induced by MS could result in increased susceptibility of the lung to bacterial infections in the setting of mechanical ventilation.