Altered lung function relates to inflammation in an acute LPS mouse model

Preclinical in vivo models of lipopolysaccharide (LPS) -induced acute lung injury are commonly used to recapitulate pathophysiological features of chronic obstructive pulmonary disease and acute exacerbations. The LPS-induced lung inflammation is well described; however, whether the inflammatory response relates temporally to specific alterations in lung function has not been elucidated.We have investigated the effects of acute LPS inhalation in mice up to 96 h post LPS. Quantitation of inflammatory cells and inflammatory mediators in bronchoalveolar lavage fluid and non-invasive and invasive lung function measurements were performed at corresponding time points. The inhibitory effect of the glucocorticoid, budesonide, on LPS-induced lung inflammation and lung function was determined.LPS inhalation induced distinct histopathological changes, and infiltration of inflammatory cells to the lungs peaked at 48 h. At this time point, significantly increased inflammatory mediators and significantly altered lung capacity and mechanics parameters were observed. Budesonide given per os prevented the LPS-induced lung inflammation and lung dysfunction.These results demonstrate a temporal relationship between the peak of inflammatory cell influx and significant impairment of lung function, suggestive of a causative role of inflammation. These results allow better understanding of the functional consequences of lung inflammation in respiratory diseases.     

Melatonin modulates allergic lung inflammation

Asthma is an inflammatory lung disease characterized by cell migration, bronchoconstriction and hyperresponsiveness, and can be induced, as an experimental model, by ovalbumin sensitization followed by a challenge. In addition to the well-known immunostimulatory effects of melatonin, research has identified some of its anti-inflammatory properties. In this study, we evaluated the influence of pinealectomy and melatonin administration on cell migration in an experimental model of allergic airway inflammation. We evaluated, in pinealectomized rats treated or not with melatonin, cell migration into the bronchoalveolar fluid, the number of cells and their proliferative activity in the bone marrow, and plasma corticosterone levels. Pinealectomy reduces, 24 hr after the challenge, the total cell number count in the lung and bone marrow cell proliferation, without changing the number of cells in the bone marrow or in the peripheral blood. This fact suggests that melatonin is important in the control of cell recruitment from the bone marrow and the migration of those cells to the lung. Melatonin administration to pinealectomized rats seems to restore the ability of cells to migrate from the bone marrow to the bronchoalveolar fluid. So, the development of specific inhibitors of melatonin would benefit patients with asthma.     

A humanized microbiota mouse model of ovalbumin-induced lung inflammation

There is increasing evidence for a role of early life gut microbiota in later development of asthma in children. In our recent study, children with reduced abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia had an increased risk of development of asthma and addition of these bacteria in a humanized mouse model reduced airway inflammation. In this Addendum, we provide additional data on the use of a humanized gut microbiota mouse model to study the development of asthma in children, highlighting the differences in immune development between germ-free mice colonized with human microbes compared to those colonized with mouse gut microbiota. We also demonstrate that there is no association between the composition of the gut microbiota in older children and the diagnosis of asthma, further suggesting the importance of the gut microbiota-immune system axis in the first 3 months of life.     

Kinetics of in vitro bronchoconstriction in an elastolytic mouse model of emphysema.

Thin-slice videomicroscopy was used to examine the kinetics of constriction in small airways in situ. Balb/C mice inhaled elastase (0-20 IU), and were then left to recover for 14 days before euthanisation and lung removal. Cholinergic responsiveness was assessed in thin lung slices. Magnitude and velocity of narrowing in response to 10(-5) M acetylcholine (ACh), as well as the full concentration-response relationship for ACh (10(-8)-10(-5) M) were assessed. In vivo exposure to elastase was accompanied by statistically significantly decreased magnitudes and velocities of contraction, but no change in the ACh concentration-response relationship. Conversely, overnight, in vitro exposure of slices from control animals to elastase (2.5 microg.mL(-1)) resulted in increased magnitudes and velocities of airway narrowing, with impaired relaxation, as well as marked tearing of the airways from the surrounding parenchyma. These changes are characteristic of decreased tethering forces on the airway wall. Thus, the lung slice technique coupled with videomicroscopic analysis of airway contraction velocities provides a powerful tool to study airway-parenchymal interactions. The elastolytic model of emphysema, which manifests with airspace enlargement and loss of parenchymal attachments, is accompanied by decreased airway contraction kinetics. The mechanism(s) underlying this loss of function remain to be elucidated.     

Resolution of acute lung injury and inflammation: a translational mouse model

Previous animal models of acute lung injury (ALI) are limited as they only reproduce part of the complex pathobiology of clinical ALI. Here we develop a translational mouse model of ALI, which not only reflects the major clinical and pathological features but also enables investigation into ALI resolution. Anaesthetised mice underwent orotracheal instillation of hydrochloric acid. During the immediate period after instillation, mice were carefully maintained with supplemental oxygen to avoid mortality. At specified time-points, lung injury was assessed by analysis of blood gases, respiratory mechanics, bronchoalveolar lavage fluid, alveolar fluid clearance and lung histology. Animals exhibited significant weight loss, decreased oxygenation, increased respiratory elastance and pulmonary inflammation (intra-alveolar leukocyte influx/cytokine levels and histological injury scores). Moreover, mice displayed alveolar-capillary barrier dysfunction/epithelial injury as reflected by increased alveolar protein, lung wet/dry weight ratio and soluble receptor for advanced glycation end-products, as well as reduced alveolar fluid clearance. These injury parameters peaked between days 1 and 3, followed by almost complete recovery over days 5-10. Histology showed evidence of fibrosis on day 10. The results indicate that this resolving model of acid aspiration represents a powerful experimental tool to investigate the injurious, inflammatory, fibrotic, and resolving and reparative processes of ALI.     

外源性间充质干细胞减轻支气管哮喘小鼠气道炎症的研究

目的 观察鸡卵清蛋白诱导小鼠支气管哮喘(简称哮喘)模型中外源性间充质干细胞(mesenchymal stem cells,MSC)在哮喘小鼠肺组织气道炎症中的作用.方法 45只雌性SPF级C57BL/6小鼠,体质量18～22 g.随机分为对照组(P:P:P)、哮喘组(O:P:O)和MSC治疗组(O:M:O).哮喘组与MSC治疗组第1天和第8天致敏,第15天、第16天和第17天使用OVA气道内滴入激发哮喘.MSC治疗组于哮喘造模第14天移植外源性MSC.对照组小鼠予PBS处理.三组小鼠于末次激发结束后24 h(第18天)处死,取支气管肺泡灌洗液上清,ELISA检测IL-5、IL-9及β-氨基己糖苷酶;支气管肺泡灌洗液细胞计数总细胞数、嗜酸粒细胞数;取肺组织行病理切片苏木精-伊红染色观察肺部气道炎症情况.结果 ①MSC下调了哮喘小鼠气道局部炎症;②MSC减轻了哮喘小鼠肺组织中的炎细胞浸润;③MSC减轻了哮喘小鼠气道中的肥大细胞脱颗粒现象;④MSC抑制了哮喘小鼠过度的Th2变态反应.结论 外源性MSC通过抑制Th2变态反应,减轻哮喘肺组织的气道炎症.     

外源性间充质干细胞减轻支气管哮喘小鼠气道炎症的研究

目的观察鸡卵清蛋白诱导小鼠支气管哮喘（简称哮喘）模型中外源性间充质干细胞（mesenehymal stem cells,MSC）在哮喘小鼠肺组织气道炎症中的作用。方法45只雌性SPF级C57BL／6小鼠,体质量18-22g。随机分为对照组（P：P：P）、哮喘组（O：P：O）和MSC治疗组（O：M：O）。哮喘组与MSC治疗组第1天和第8天致敏,第15天、第16天和第17天使用OVA气道内滴入激发哮喘。MSC治疗组于哮喘造模第14天移植外源性MSC。对照组小鼠予PBS处理。三组小鼠于末次激发结束后24h（第18天）处死,取支气管肺泡灌洗液上清,ELISA检测IL-5、IL-9及β-氨基己糖苷酶;支气管肺泡灌洗液细胞计数总细胞数、嗜酸粒细胞数;取肺组织行病理切片苏木精-伊红染色观察肺部气道炎症情况。结果①MSC下调了哮喘小鼠气道局部炎症;②MSC减轻了哮喘小鼠肺组织中的炎细胞浸润;③MSC减轻了哮喘小鼠气道中的肥大细胞脱颗粒现象;④MSC抑制了哮喘小鼠过度的Th2变态反应。结论外源性MSC通过抑制Th2变态反应,减轻哮喘肺组织的气道炎症。     

Adenosine-mediated early preconditioning in mouse: protective signaling and concentration dependent effects

OBJECTIVES: Signaling in adenosine-mediated preconditioning is controversial. We examined roles of mitochondrial (mito) K(ATP) channels, protein kinase C (PKC) and nitric oxide (NO). METHODS: Langendorff perfused C57/Bl6 mouse hearts were subjected to 20 min ischemia and 45 min reperfusion. Effects of adenosine-mediated preconditioning were assessed in the absence and presence of signaling inhibitors. RESULTS: Control hearts recovered 70+/-2 mmHg ventricular pressure, and released 18.1+/-2.0 IU/g lactate dehydrogenase (LDH). Preconditioning with 10 microM adenosine limited necrosis (10.6+/-1.4 IU/g) without modifying contractility (72+/-2 mmHg) whereas 50 microM adenosine reduced necrosis (10.3+/-1.6 IU/g) and contractile dysfunction (91+/-2 mmHg). All protective effects of 10 and 50 microM adenosine were abrogated by mito K(ATP) channel blockade with 100 microM 5-hydroxydecanoate (5-HD) during the 'trigger' phase, but unaltered by PKC or NO synthase inhibition with 3 microM chelerythrine or 100 microM N(G)-nitro-L-arginine methyl ester (L-NAME), respectively. Protection against necrosis was eliminated by 5-HD but unaltered by chelerythrine or L-NAME during the 'mediation' phase (ischemia-reperfusion). Reduced contractile dysfunction with 50 microM adenosine was partially sensitive to 5-HD and chelerythrine, and only eliminated by co-infusion of the inhibitors. CONCLUSIONS: Adenosine-mediated preconditioning is dose-dependent with high level stimulation reducing contractile dysfunction in addition to necrosis. Preconditioning is triggered by a mito K(ATP) channel dependent process independently of PKC and NO. Subsequent protection against necrosis is also mediated by a mito K(ATP) channel dependent process independent of PKC and NO. In contrast, functional protection may be mediated by parallel mito K(ATP) and PKC dependent paths.     

Content and localization of leukotriene C4 in lung tissue during biphasic allergic bronchoconstriction in the guinea pig]

Leukotriene C4 (LTC4) is a very potent bronchoconstrictor, and is believed to be an important mediator during immediate (IAR) and late asthmatic response (LAR). No direct measurement of LTC4 in lung tissue during IAR and LAR has been reported, however, and its localized site in the lung remains unclear. In an effort to clarify these issues, the content of LTC4 in lung tissue was evaluated at the onset of antigen-induced IAR and LAR, and the distribution of LTC4 was examined by immunohistochemistry. IAR and LAR were induced by inhalation of aerosolized ovalbumin (OA) in conscious guinea pigs. The development of IAR and LAR following inhaled OA exposure was determined in sensitized guinea pigs by measurement of respiratory resistance using the oscillation method. LTC4 in lung tissue was measured by radioimmunoassay at six different stages (S1: non-treated group; S2: group before OA-challenge following sensitization; S3: IAR group; S4: group two hours after IAR; S5: LAR-positive group; S6: LAR-negative group). For immunohistochemistry, non-treated guinea pigs and the sensitized animals at the onset of LAR were used. Lung sections were stained with anti-LTC4 antibody by avidin biotin peroxidase complex method (ABC method). About 70% of the guinea pigs displayed IAR, followed by LAR that peaked at 6-20 hours after OA challenge. The LTC4 content in lung tissue was significantly increased (p less than 0.01) at the onset of IAR, but was significantly decreased (p less than 0.01) after two hours, and significantly increased (p less than 0.01) at the onset of LAR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of inflammation in mouse lung tumorigenesis: a review

Peritumoral and intratumoral macrophages are associated with human and mouse lung cancer The mouse model allows manipulation of the macrophage population to experimentally evaluate its contribution to tumor growth. Genetic and pharmacologic strategies also permit testing the invol vement of specific inflammatory mediators in tumor progression. Among those endogenous mediators thus identified are interleukin (IL)-10, glucocorticoids, prostacyclin, nitric oxide, and surfactant apoprotein D (SP-D); serum SP-D levels are a useful biomarker to monitor tumor growth rate. The importance of understanding the mutually antagonistic roles of individual prostaglandins downstream from cycloxygenase (COX) and how this affects the efficacy of COX-inhibitory drugs is discussed. Promising drug candidates include synthetic glucocorticoids such as budesonide and the sulfone derivative of sulindac, apotosyn.     

Airway inflammation induces anxiety-like behavior through neuroinflammatory,neurochemical, and neurometabolic changes in an allergic asthma model

Metabolic Brain Disease - Allergic asthma is characterized by chronic airway inflammation and is constantly associated with anxiety disorder. Recent studies showed bidirectional interaction between...     

Lung parenchyma remodeling in a murine model of chronic allergic inflammation

This study tested the hypotheses that chronic allergic inflammation induces not only bronchial but also lung parenchyma remodeling, and that these histologic changes are associated with concurrent changes in respiratory mechanics. For this purpose, airway and lung parenchyma remodeling were evaluated by quantitative analysis of collagen and elastin, immunohistochemistry (smooth-muscle actin expression, eosinophil, and dendritic cell densities), and electron microscopy. In vivo (airway resistance, viscoelastic pressure, and static elastance) and in vitro (tissue elastance, resistance, and hysteresivity) respiratory mechanics were also analyzed. BALB/c mice were sensitized with ovalbumin and exposed to repeated ovalbumin challenges. A marked eosinophilic infiltration was seen in lung parenchyma and in large and distal airways. Neutrophils, lymphocytes, and dendritic cells also infiltrated the lungs. There was subepithelial fibrosis, myocyte hypertrophy and hyperplasia, elastic fiber fragmentation, and increased numbers of myofibroblasts in airways and lung parenchyma. Collagen fiber content was increased in the alveolar walls. The volume proportion of smooth muscle-specific actin was augmented in distal airways and alveolar duct walls. Airway resistance, viscoelastic pressure, static elastance, and tissue elastance and resistance were significantly increased. In conclusion, prolonged allergen exposure induced remodeling not only of the airway wall but also of the lung parenchyma, leading to in vivo and in vitro mechanical changes.