Enhanced Lung Inflammatory Response in Whole-body Compared to Nose-only Cigarette Smoke-exposed Mice

Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by a progressive and abnormal inflammatory response in the lungs, mainly caused by cigarette smoking. Animal models exposed to cigarette smoke (CS) are used to mimic human COPD but the use of different CS protocols makes it difficult to compare the immunological and structural consequences of using a nose-only or whole-body CS exposure system. We hypothesized that when using a standardized CS exposure protocol based on particle density and CO (carbon monoxide) levels, the whole-body CS exposure system would generate a more severe inflammatory response than the nose-only system, due to possible sensitization, uptake of gases through the skin or uptake of tar particles stuck on the skin via grooming. Methods: In this study focusing on early COPD, mice were exposed twice daily 5 days a week to CS either with a nose-only or whole-body exposure system for 14 weeks to assess lung remodeling and inflammation. Data was analyzed with a one-way ANOVA with Bonferroni post-hoc test or Kruskal-Wallis with Dunn’s test for multiple comparison depending on respectively parametric or non-parametric datasets.Results: Both CS exposure systems induced a similar degree of lung function impairment and morphological alterations. Interestingly, an enhanced lymphoid presence in the bronchoalveolar lavage and lymph nodes with a higher mRNA expression of interleukin 6 and keratinocyte chemoattractant in the lungs were found with the whole-body system. Conclusion: Our data indicate that the inflammatory outcomes are more severe in the whole-body CS exposure compared to the nose-only system, but lung remodeling and lung function impairment are similarly affected. These observations can assist researchers to make an appropriate choice between the two CS exposure systems in designing their future studies in early drug interventions.

Inhibition of CD44 attenuates pressure overload-induced cardiac and lung inflammation, fibrosis, and heart failure progression

Background Inflammation contributes to heart failure (HF) development and progression. CD44 is a member of the hyaluronate receptor family of cell adhesion molecules, which regulates tissue inflammation and fibrosis through modulating macrophage and lymphocyte migration and homing in several diseases. Here we evaluated the role and cellular mechanism of CD44 in regulating transverse aortic constriction (TAC)-induced HF development and progression in mice. Methods and results C57/B6 background CD44 KO and wild type mice (6–8 weeks) were subjected to TAC to evaluate the effect of CD44 on the development of TAC-induced LV hypertrophy and cardiac dysfunction. Due to the rapid response to TAC, Balb/c mice (6–8 weeks) were used to determine the effect of CD44 on the progression of TAC-induced congestive heart failure. We found that CD44 expression is dramatically increased in left ventricular (LV) tissues obtained from HF patients and mice. While CD44 gene knockout (KO) has no detectable effect on cardiac structure and function under control conditions, CD44 KO mice were protected from TAC-induced LV inflammation, fibrosis, hypertrophy, dysfunction, and lung remodeling as compared with wild type mice. In addition, we found that inhibition of CD44 signaling with blocking antibodies (Abs) significantly attenuated the transition from LV failure to lung remodeling, and right ventricular hypertrophy in mice with existing HF. Conclusions These data identify an important role of CD44 in attenuating cardiac and lung inflammation, fibrosis, HF development, and HF progression, suggesting that inhibition of CD44 signaling may be useful in preventing and treating HF. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Chinese National Natural Science Foundation Grants and American Heart Association

Exercise Improves Lung Inflammation, but Not Lung Remodeling and Mechanics in a Model of Bleomycin-Induced Lung Fibrosis

Introduction. Moderate aerobic exercise training accelerates the resolution of lung fibrosis in a model of bleomycin-induced pulmonary fibrosis. However, whether it can inhibit the development of lung fibrosis is unknown. Materials and Methods. C57Bl/6 mice were distributed into four groups: Control (Co), Exercise (Exe), Bleomycin (Bleo), and Bleomycin+Exercise (Bleo+Exe). A single bleomycin dose (1.5 UI/kg) was administered orotracheally and treadmill exercise started in the same day, enduring for 4 weeks, 5x/week, 60 minutes/session, at moderate intensity. Lung mechanics, systemic and pulmonary inflammation, and lung remodeling were evaluated. Lung homogenates were used to evaluate the antioxidant status. Results. Total cells, macrophages, lymphocytes, and neutrophils numbers, in agreement with IL-6 levels, were higher in the BAL and serum of Bleo group, compared to other groups. In addition, lung levels of LTB4 in Bleo were higher than other groups, whereas SOD activity and nitric oxide levels in exercised groups (Exe and Exe+Bleo) compared to the Bleo group. Lung GPX activity was lower in Bleo and Exe+Bleo groups compared to others. Exe and Exe+Bleo groups also showed higher IL-10 expression by lung macrophages than other groups, whereas TGF-β expression was higher in Exe, Bleo, and Exe+Bleo groups compared to control. CCR7 expression was induced only in the Exe group. However, exercise did not improve lung remodeling and mechanics, or serum and pulmonary levels of VEGF, IGF-1, and TGF-β. Conclusion. Aerobic exercise training initiated concomitantly with induction of pulmonary fibrosis reduces lung and systemic inflammation but fails to inhibit lung fibrosis and mechanics impairment.

Inhibition of the stem cell factor 248 isoform attenuates the development of pulmonary remodeling disease

Stem cell factor (SCF) and its receptor c-kit have been implicated in inflammation, tissue remodeling, and fibrosis. Ingenuity Integrated Pathway Analysis of gene expression array data sets showed an upregulation of SCF transcripts in idiopathic pulmonary fibrosis (IPF) lung biopsies compared with tissue from nonfibrotic lungs that are further increased in rapid progressive disease. SCF248, a cleavable isoform of SCF, was abundantly and preferentially expressed in human lung fibroblasts and fibrotic mouse lungs relative to the SCF220 isoform. In fibroblast-mast cell coculture studies, blockade of SCF248 using a novel isoform-specific anti-SCF248 monoclonal antibody (anti-SCF248), attenuated the expression of COL1A1, COL3A1, and FN1 transcripts in cocultured IPF but not normal lung fibroblasts. Administration of anti-SCF248 on days 8 and 12 after bleomycin instillation in mice significantly reduced fibrotic lung remodeling and col1al, fn1, acta2, tgfb, and ccl2 transcript expression. In addition, bleomycin increased numbers of c-kit+ mast cells, eosinophils, and ILC2 in lungs of mice, whereas they were not significantly increased in anti-SCF248-treated animals. Finally, mesenchymal cell-specific deletion of SCF significantly attenuated bleomycin-mediated lung fibrosis and associated fibrotic gene expression. Collectively, these data demonstrate that SCF is upregulated in diseased IPF lungs and blocking SCF248 isoform significantly ameliorates fibrotic lung remodeling in vivo suggesting that it may be a therapeutic target for fibrotic lung diseases.

Maternal Obesity in Mice Exacerbates the Allergic Inflammatory Response in the Airways of Male Offspring

It was previously demonstrated that non-allergen-sensitized rodents born to mothers exposed to a high-fat diet (HFD) spontaneously develop lower respiratory compliance and higher respiratory resistance. In the present study, we sought to determine if mice born to mothers consuming HFD would exhibit changes in inflammatory response and lung remodeling when subjected to ovalbumin (OVA) sensitization/challenge in adult life. Mice born to dams consuming either HFD or standard chow had increased bronchoalveolar lavage (BAL) levels of IL-1β, IL-4, IL-5, IL-10, IL-13, TNF-α and TGF-β1 after challenge with OVA. IL-4, IL-13, TNF-α and TGF-β1 levels were further increased in the offspring of HFD-fed mothers. Mice born to obese dams also had exacerbated values of leukocyte infiltration in lung parenchyma, eosinophil and neutrophil counts in BAL, mucus overproduction and collagen deposition. The programming induced by maternal obesity was accompanied by increased expression of miR-155 in peripheral-blood mononuclear cells and reduced miR-133b in trachea and lung tissue in adult life. Altogether, the present data support the unprecedented notion that the progeny of obese mice display exacerbated responses to sensitization/challenge with OVA, leading to the intensification of the morphological changes of lung remodeling. Such changes are likely to result from long-lasting changes in miR-155 and miR-133b expression.