scholarly journals Experimental progressive emphysema in BALB/cJ mice as a model for chronic alveolar destruction in humans

2015 ◽  
Vol 309 (7) ◽  
pp. L662-L676 ◽  
Author(s):  
Nathachit Limjunyawong ◽  
John M. Craig ◽  
H. A. Daniel Lagassé ◽  
Alan L. Scott ◽  
Wayne Mitzner
Keyword(s):  
Body Weight Loss ◽  
Inflammatory Cells ◽  
Interferon Γ ◽  
Mouse Strains ◽  
Chronic Obstructive ◽  
Dependent Manner ◽  
Obstructive Pulmonary Disease ◽  
Alveolar Tissue ◽  
Dose Dependent ◽  
Experimental Emphysema

Emphysema, one of the major components of chronic obstructive pulmonary disease (COPD), is characterized by the progressive and irreversible loss of alveolar lung tissue. Even though >80% of COPD cases are associated with cigarette smoking, only a relatively small proportion of smokers develop emphysema, suggesting a potential role for genetic factors in determining individual susceptibility to emphysema. Although strain-dependent effects have been shown in animal models of emphysema, the molecular basis underlying this intrinsic susceptibility is not fully understood. In this present study, we investigated emphysema development using the elastase-induced experimental emphysema model in two commonly used mouse strains, C57BL/6J and BALB/cJ. The results demonstrate that mice with different genetic backgrounds show disparate susceptibility to the development of emphysema. BALB/cJ mice were found to be much more sensitive than C57BL/6J to elastase injury in both a dose-dependent and time-dependent manner, as measured by significantly higher mortality, greater body weight loss, greater decline in lung function, and a greater loss of alveolar tissue. The more susceptible BALB/cJ strain also showed the persistence of inflammatory cells in the lung, especially macrophages and lymphocytes. A comparative gene expression analysis following elastase-induced injury showed BALB/cJ mice had elevated levels of il17A mRNA and a number of classically (M1) and alternatively (M2) activated macrophage genes, whereas the C57BL/6J mice demonstrated augmented levels of interferon-γ. These findings suggest a possible role for these cellular and molecular mediators in modulating the severity of emphysema and highlight the possibility that they might contribute to the heterogeneity observed in clinical emphysema outcomes.

scholarly journals Herbal Medication, Macmoondong Decoction, Attenuates LPS-Induced COPD in Small Airways via TGF-β, CCL-2, and CXCL1

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Soon-Young Lee ◽  
Bossng Kang ◽  
Chun-Sik Bae ◽  
Seung-Sik Cho ◽  
Dae-Hun Park
Keyword(s):  
Morphological Changes ◽  
World Health ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Dependent Manner ◽  
Obstructive Pulmonary Disease ◽  
Cytokines And Chemokines ◽  
Incurable Disease ◽  
Health Organization ◽  
Dose Dependent

Chronic obstructive pulmonary disease (COPD) is an incurable disease related to the respiratory system. A 2017 report by the World Health Organization stated that it was the third most common cause of death in 2015. Macmoondong decoction is a prescription that has been used widely in Korea for the treatment of respiratory diseases, but there have been few investigations into the therapeutic mechanism. To investigate the anti-COPD effect of macmoondong decoction, the animals were divided into five treatment groups: control; COPD-induced control; Spiriva; 150 mg/kg macmoondong decoction; and 1500 mg/kg macmoondong decoction. Changes typically observed in COPD, such as the populations of WBC and neutrophils in BALF, the level of IgE in serum, morphological changes, the DNA levels, and the protein expression of cytokines and chemokines (TGF-β, CCL-2, CXCL1, and CXCL11) in the pulmonary system, were evaluated. Macmoondong decoction inhibited the populations of WBC and neutrophils in BALF and the level of IgE in serum. Dose-dependent prevention of the pulmonary morphological changes, such as emphysema and airway fibrosis, was observed. Macmoondong decoction suppressed the expression of DNA and proteins related to the occurrence of COPD, such as TGF-β, CCL-2, CXCL1, and CXCL11. In particular, the expression of TGF-β, CCL-2, and CXCL1 was significantly suppressed by 1500 mg/kg macmoondong decoction treatment compared with Spiriva treatment. Macmoondong decoction exerted an anti-COPD effect, and the mechanism of its action may be the suppression of TGF-β, CCL-2, CXCL1, and CXCL11 expression, which occurred in a dose-dependent manner. The mechanism of action of macmoondong decoction may be the dose-dependent suppression of TGF-β, CCL-2, CXCL1, and CXCL11, with TGF-β, CCL-2, and CXCL1 as the potential key factors involved in COPD suppression.

scholarly journals Hesperetin, a Selective Phosphodiesterase 4 Inhibitor, Effectively Suppresses Ovalbumin-Induced Airway Hyperresponsiveness without Influencing Xylazine/Ketamine-Induced Anesthesia

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Chung-Hung Shih ◽  
Ling-Hung Lin ◽  
Hsin-Te Hsu ◽  
Kuo-Hsien Wang ◽  
Chi-Yin Lai ◽  
...  
Keyword(s):  
Airway Hyperresponsiveness ◽  
Immunoglobulin E ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Interferon Γ ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Phosphodiesterase 4 ◽  
Specific Immunoglobulin E ◽  
Factor Α

Hesperetin, a selective phosphodiesterase (PDE)4 inhibitor, is present in the traditional Chinese medicine, “Chen Pi.” Therefore, we were interested in investigating its effects on ovalbumin- (OVA-) induced airway hyperresponsiveness, and clarifying its rationale for ameliorating asthma and chronic obstructive pulmonary disease (COPD). Hesperetin was revealed to have a therapeutic (PDE4H/PDE4L) ratio of >11. Hesperetin (10 ~ 30 μmol/kg, intraperitoneally (i.p.)) dose-dependently and significantly attenuated the airway hyperresponsiveness induced by methacholine. It also significantly suppressed the increases in total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF). It dose-dependently and significantly suppressed total and OVA-specific immunoglobulin E levels in the BALF and serum. However, hesperetin did not influence xylazine/ketamine-induced anesthesia, suggesting that hesperetin has few or no emetic effects. In conclusion, the rationales for ameliorating allergic asthma and COPD by hesperetin are anti-inflammation, immunoregulation, and bronchodilation.

scholarly journals Loss of IL-33 enhances elastase-induced and cigarette smoke extract-induced emphysema in mice

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daisuke Morichika ◽  
Akihiko Taniguchi ◽  
Naohiro Oda ◽  
Utako Fujii ◽  
Satoru Senoo ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Intratracheal Instillation ◽  
Inflammatory Cells ◽  
Cigarette Smoke Extract ◽  
Lymphoid Cells ◽  
Chronic Obstructive ◽  
Porcine Pancreas ◽  
Obstructive Pulmonary Disease ◽  
Quantitative Morphometry ◽  
Cytokines And Chemokines

Abstract Background IL-33, which is known to induce type 2 immune responses via group 2 innate lymphoid cells, has been reported to contribute to neutrophilic airway inflammation in chronic obstructive pulmonary disease. However, its role in the pathogenesis of emphysema remains unclear. Methods We determined the role of interleukin (IL)-33 in the development of emphysema using porcine pancreas elastase (PPE) and cigarette smoke extract (CSE) in mice. First, IL-33−/− mice and wild-type (WT) mice were given PPE intratracheally. The numbers of inflammatory cells, and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates, were analyzed; quantitative morphometry of lung sections was also performed. Second, mice received CSE by intratracheal instillation. Quantitative morphometry of lung sections was then performed again. Results Intratracheal instillation of PPE induced emphysematous changes and increased IL-33 levels in the lungs. Compared to WT mice, IL-33−/− mice showed significantly greater PPE-induced emphysematous changes. No differences were observed between IL-33−/− and WT mice in the numbers of macrophages or neutrophils in BAL fluid. The levels of hepatocyte growth factor were lower in the BAL fluid of PPE-treated IL-33−/− mice than WT mice. IL-33−/− mice also showed significantly greater emphysematous changes in the lungs, compared to WT mice, following intratracheal instillation of CSE. Conclusion These observations suggest that loss of IL-33 promotes the development of emphysema and may be potentially harmful to patients with COPD.

scholarly journals Bactericidal/Permeability-Increasing Protein Preeminently Mediates Clearance of Pseudomonas aeruginosa In Vivo via CD18-Dependent Phagocytosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jomkuan Theprungsirikul ◽  
Sladjana Skopelja-Gardner ◽  
Ashley S. Burns ◽  
Rachel M. Wierzbicki ◽  
William F. C. Rigby
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Critical Role ◽  
Chronic Obstructive ◽  
Dependent Manner ◽  
Opsonic Activity ◽  
Obstructive Pulmonary Disease ◽  
Neutrophil Dysfunction ◽  
Chronic Lung Infection

Chronic Pseudomonas aeruginosa infection mysteriously occurs in the airways of patients with cystic fibrosis (CF), bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD) in the absence of neutrophil dysfunction or neutropenia and is strongly associated with autoimmunity to bactericidal permeability-increasing protein (BPI). Here, we define a critical role for BPI in in vivo immunity against P. aeruginosa. Wild type and BPI-deficient (Bpi-/-) mice were infected with P. aeruginosa, and bacterial clearance, cell infiltrates, cytokine production, and in vivo phagocytosis were quantified. Bpi-/- mice exhibited a decreased ability to clear P. aeruginosa in vivo in concert with increased neutrophil counts and cytokine release. Bpi-/- neutrophils displayed decreased phagocytosis that was corrected by exogenous BPI in vitro. Exogenous BPI also enhanced clearance of P. aeruginosa in Bpi-/- mice in vivo by increasing P. aeruginosa uptake by neutrophils in a CD18-dependent manner. These data indicate that BPI plays an essential role in innate immunity against P. aeruginosa through its opsonic activity and suggest that perturbations in BPI levels or function may contribute to chronic lung infection with P. aeruginosa.

scholarly journals Regenerative pharmacology for COPD: breathing new life into old lungs

Thorax ◽  
2019 ◽  
Vol 74 (9) ◽  
pp. 890-897 ◽  
Author(s):  
John-Poul Ng-Blichfeldt ◽  
Reinoud Gosens ◽  
Charlotte Dean ◽  
Mark Griffiths ◽  
Matthew Hind
Keyword(s):  
Large Scale ◽  
Biologically Active ◽  
Health Concern ◽  
Chronic Obstructive ◽  
Small Airways ◽  
Obstructive Pulmonary Disease ◽  
Molecular Control ◽  
Mild Disease ◽  
Peripheral Airway ◽  
Alveolar Tissue

Chronic obstructive pulmonary disease (COPD) is a major global health concern with few effective treatments. Widespread destruction of alveolar tissue contributes to impaired gas exchange in severe COPD, and recent radiological evidence suggests that destruction of small airways is a major contributor to increased peripheral airway resistance in disease. This important finding might in part explain the failure of conventional anti-inflammatory treatments to restore lung function even in patients with mild disease. There is a clear need for alternative pharmacological strategies for patients with COPD/emphysema. Proposed regenerative strategies such as cell therapy and tissue engineering are hampered by poor availability of exogenous stem cells, discouraging trial results, and risks and cost associated with surgery. An alternative therapeutic approach is augmentation of lung regeneration and/or repair by biologically active factors, which have potential to be employed on a large scale. In favour of this strategy, the healthy adult lung is known to possess a remarkable endogenous regenerative capacity. Numerous preclinical studies have shown induction of regeneration in animal models of COPD/emphysema. Here, we argue that given the widespread and irreversible nature of COPD, serious consideration of regenerative pharmacology is necessary. However, for this approach to be feasible, a better understanding of the cell-specific molecular control of regeneration, the regenerative potential of the human lung and regenerative competencies of patients with COPD are required.

Protective Effect of Reduced Glutathione against CIS-Dichlorodiammine Platinum (II)–Induced Nephrotoxicity and Lethal Toxicity

1983 ◽  
Vol 69 (2) ◽  
pp. 105-111 ◽  
Author(s):  
Franco Zunino ◽  
Odoardo Tofanetti ◽  
Adriana Besati ◽  
Ennio Cavalletti ◽  
Giuseppina Savi
Keyword(s):  
Reduced Glutathione ◽  
Body Weight Loss ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Antitumor Effects ◽  
Partial Protection ◽  
Lethal Toxicity ◽  
Sprague Dawley Rats ◽  
Serum Blood Urea Nitrogen ◽  
Dose Dependent

Pretreatment of Swiss mice and Sprague-Dawley rats with glutathione (GSH) reduced the acute lethal toxicity of cis-dichlorodiammine platinum (II) (cis-DDP) in a dose-dependent manner. The protection was accompanied by reduction of both body weight loss and by reduction of nephrotoxicity, as measured by a rise in serum blood urea nitrogen (BUN), creatinine levels and by histopathologic changes, which occurred 4 days following cis-DDP treatment. The antitumor effects of cis-DDP on experimental tumor models (P388 and Gross leukemia) were not significantly altered by GSH treatment. It is suggested that the partial protection by GSH from acute toxicity of the antitumor drug is directly related to protection of renal function.

scholarly journals Impact of aging on inflammatory and immune responses during elastin peptide-induced murine emphysema

2019 ◽  
Vol 316 (4) ◽  
pp. L608-L620 ◽  
Author(s):  
Alexandre Pierre ◽  
Flora Lemaire ◽  
Aïda Meghraoui-Kheddar ◽  
Sandra Audonnet ◽  
Stéphanie Héry-Huynh ◽  
...  
Keyword(s):  
Immune Response ◽  
Structural Changes ◽  
Interferon Γ ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Specific Memory ◽  
Cell Clones ◽  
The Matrix ◽  
Key Factor ◽  
Lymphocytic Infiltrates

Deterioration of lung functions and degradation of elastin fibers with age are accelerated during chronic obstructive pulmonary disease (COPD). Excessive genesis of soluble elastin peptides (EP) is a key factor in the pathophysiology of COPD. We have previously demonstrated that 6-wk-old mice exhibited emphysematous structural changes associated with proinflammatory immune response after EP instillation. In this study, we investigated the consequences of aging on inflammatory, immune, and histological criteria associated with murine emphysema progression after EP exposure. Young (6 wk old) and elderly (15 mo old) C57BL/6J mice were endotracheally instilled with EP, and, at various time points after treatment, the inflammatory cell profiles from bronchoalveolar lavage fluids (BALF) and the T-lymphocyte phenotypes, at local and systemic levels, were analyzed by flow cytometry. Lungs were also prepared to allow morphological and histological analysis by confocal microscopy. Elderly mice exhibited an earlier development of pulmonary emphysema, characterized by an increase of the inflammatory and lymphocytic infiltrates, extracellular matrix breakdown, and airspace enlargement compared with young mice. This age-dependent parenchymal tissue remodeling was associated with an increase of the matrix metalloproteinase expressions and desmosine levels in BALF and/or sera of EP-treated mice. In addition, both the proportion of CD4+CD28− and CD8+CD28− T cells in the tissues of EP-treated mice and the interferon-γ levels in the EP-specific memory T-cell clones were significantly higher in elderly versus younger mice. This study demonstrates that aging accelerates emphysema development and that this effect is linked to increased EP production and their effects on inflammatory and immune response.

scholarly journals Secretory Leucocyte Protease Inhibitor Inhibits Interferon-γ-induced Cathepsin S Expression

2007 ◽  
Vol 282 (46) ◽  
pp. 33389-33395 ◽  
Author(s):  
Patrick Geraghty ◽  
Catherine M. Greene ◽  
Michael O'Mahony ◽  
Shane J. O'Neill ◽  
Clifford C. Taggart ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Protease Inhibitor ◽  
Pulmonary Disease ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Interferon Γ ◽  
Secretory Leukocyte Protease Inhibitor ◽  
Cathepsin S ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

We have demonstrated that bronchoalveolar lavage fluid from chronic obstructive pulmonary disease patients contains higher levels of interferon-γ compared with controls. Interferon-γ is a potent inducer of various cathepsins and matrix metalloproteases. Therefore, we postulated that interferon-γ could induce protease expression by macrophages in acute and chronic lung disease. Chronic obstructive pulmonary disease patients had greater levels of cathepsin S and matrix metalloprotease-12 in their bronchoalveolar lavage fluid. Macrophages incubated with chronic obstructive pulmonary disease bronchoalveolar lavage fluid exhibited increased expression of cathepsin S and matrix metalloprotease-12, which was inhibited by the addition of interferon-γ-neutralizing immunoglobulin. Human secretory leukocyte protease inhibitor is an 11.7-kDa cationic non-glycosylated antiprotease synthesized and secreted by cells at the site of inflammation. We have demonstrated that secretory leukocyte protease inhibitor can inhibit interferon-γ-induced cathepsin S production by macrophages. Pretreatment of macrophages with secretory leukocyte protease inhibitor inhibited interferon-γ-induced inhibitor κB β degradation and activation of nuclear factor κB. Secretory leukocyte protease inhibitor may prove to be therapeutically important as a potential inhibitor of protease expression in chronic obstructive pulmonary disease.

scholarly journals Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice

2015 ◽  
Vol 308 (1) ◽  
pp. L96-L103 ◽  
Author(s):  
Loes E. M. Kistemaker ◽  
Ronald P. van Os ◽  
Albertina Dethmers-Ausema ◽  
I. Sophie T. Bos ◽  
Machteld N. Hylkema ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cigarette Smoke ◽  
Neutrophil Migration ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Chronic Obstructive ◽  
Wild Type ◽  
Obstructive Pulmonary Disease ◽  
Neutrophilic Inflammation ◽  
Relative Contribution

Anticholinergics, blocking the muscarinic M3 receptor, are effective bronchodilators for patients with chronic obstructive pulmonary disease. Recent evidence from M3 receptor-deficient mice (M3R−/−) indicates that M3 receptors also regulate neutrophilic inflammation in response to cigarette smoke (CS). M3 receptors are present on almost all cell types, and in this study we investigated the relative contribution of M3 receptors on structural cells vs. inflammatory cells to CS-induced inflammation using bone marrow chimeric mice. Bone marrow chimeras (C56Bl/6 mice) were generated, and engraftment was confirmed after 10 wk. Thereafter, irradiated and nonirradiated control animals were exposed to CS or fresh air for four consecutive days. CS induced a significant increase in neutrophil numbers in nonirradiated and irradiated control animals (4- to 35-fold). Interestingly, wild-type animals receiving M3R−/− bone marrow showed a similar increase in neutrophil number (15-fold). In contrast, no increase in the number of neutrophils was observed in M3R−/− animals receiving wild-type bone marrow. The increase in keratinocyte-derived chemokine (KC) levels was similar in all smoke-exposed groups (2.5- to 5.0-fold). Microarray analysis revealed that fibrinogen-α and CD177, both involved in neutrophil migration, were downregulated in CS-exposed M3R−/− animals receiving wild-type bone marrow compared with CS-exposed wild-type animals, which was confirmed by RT-qPCR (1.6–2.5 fold). These findings indicate that the M3 receptor on structural cells plays a proinflammatory role in CS-induced neutrophilic inflammation, whereas the M3 receptor on inflammatory cells does not. This effect is probably not mediated via KC release, but may involve altered adhesion and transmigration of neutrophils via fibrinogen-α and CD177.

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