Cigarette smoke-induced pulmonary emphysema in scid-mice. Is the acquired immune system required?

Respiratory Research, Dec 2005

Background Chronic obstructive pulmonary disease is associated with a chronic inflammatory response of the host to chronic exposure to inhaled toxic gases and particles. Although inflammatory cells of both the innate and adaptive immune system infiltrate the lungs in pulmonary emphysema and form lymphoid follicles around the small airways, the exact role of the acquired immune system in the pathogenesis of emphysema is not known. Methods In this study, wild type Balb/c mice and immunodeficient scid mice – which lack functional B- and T-cells – were exposed to mainstream cigarette smoke (CS) for 5 weeks or 6 months. Results Subacute CS-exposure for 5 weeks significantly increased innate inflammatory cells (neutrophils, macrophages and dendritic cells) in the bronchoalveolar lavage (BAL) fluid of wild type mice and scid mice, which correlated with the CS-induced upregulation of the chemokines Monocyte Chemotactic Protein-1, Macrophage Inflammatory Protein-3α and KC (= mouse Interleukin-8). Chronic CS-exposure for 6 months significantly increased the number of neutrophils, macrophages, dendritic cells, CD4+ and CD8+ T-lymphocytes in BAL fluid and lungs of wild type mice compared to air-exposed littermates, and augmented the size and number of peribronchial lymphoid follicles. In contrast, neither B-lymphocytes, nor T-lymphocytes, nor lymphoid follicles could be discerned in the lungs of air- or CS-exposed scid mice. Importantly, chronic CS-exposure induced pulmonary emphysema in both wild type animals and scid mice, as evidenced by a significant increase in the mean linear intercept and the destructive index of CS-exposed versus air-exposed animals. The CS-induced emphysema was associated with increased mRNA expression of matrix metalloproteinase-12 in the lungs and increased protein levels of Tumor Necrosis Factor-α in the BAL fluid of CS-exposed Balb/c and scid mice compared to air-exposed littermates. Conclusion This study suggests that the adaptive immune system is not required per se to develop pulmonary emphysema in response to chronic CS-exposure, since emphysema can be induced in scid mice, which lack lymphoid follicles as well as functional B- and T-cells.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://respiratory-research.com/content/pdf/1465-9921-6-147.pdf

Cigarette smoke-induced pulmonary emphysema in scid-mice. Is the acquired immune system required?

An I D'hulst 0 Tania Maes 0 Ken R Bracke 0 Ingel K Demedts 0 Kurt G Tournoy 0 Guy F Joos 0 Guy G Brusselle 0 0 Address: Department of Respiratory Diseases, Ghent University Hospital , Ghent , Belgium Background: Chronic obstructive pulmonary disease is associated with a chronic inflammatory response of the host to chronic exposure to inhaled toxic gases and particles. Although inflammatory cells of both the innate and adaptive immune system infiltrate the lungs in pulmonary emphysema and form lymphoid follicles around the small airways, the exact role of the acquired immune system in the pathogenesis of emphysema is not known. Methods: In this study, wild type Balb/c mice and immunodeficient scid mice - which lack functional B- and T-cells - were exposed to mainstream cigarette smoke (CS) for 5 weeks or 6 months. Results: Subacute CS-exposure for 5 weeks significantly increased innate inflammatory cells (neutrophils, macrophages and dendritic cells) in the bronchoalveolar lavage (BAL) fluid of wild type mice and scid mice, which correlated with the CS-induced upregulation of the chemokines Monocyte Chemotactic Protein-1, Macrophage Inflammatory Protein-3 and KC (= mouse Interleukin-8). Chronic CS-exposure for 6 months significantly increased the number of neutrophils, macrophages, dendritic cells, CD4+ and CD8+ T-lymphocytes in BAL fluid and lungs of wild type mice compared to air-exposed littermates, and augmented the size and number of peribronchial lymphoid follicles. In contrast, neither B-lymphocytes, nor T-lymphocytes, nor lymphoid follicles could be discerned in the lungs of air- or CS-exposed scid mice. Importantly, chronic CS-exposure induced pulmonary emphysema in both wild type animals and scid mice, as evidenced by a significant increase in the mean linear intercept and the destructive index of CSexposed versus air-exposed animals. The CS-induced emphysema was associated with increased mRNA expression of matrix metalloproteinase-12 in the lungs and increased protein levels of Tumor Necrosis Factor- in the BAL fluid of CS-exposed Balb/c and scid mice compared to airexposed littermates. Conclusion: This study suggests that the adaptive immune system is not required per se to develop pulmonary emphysema in response to chronic CS-exposure, since emphysema can be induced in scid mice, which lack lymphoid follicles as well as functional B- and T-cells. - Background Chronic obstructive pulmonary disease (COPD) is currently listed as the fifth leading cause of death in the world, and is also an important cause of chronic disability and permanent impairment, representing a major economic and social burden worldwide [1,2]. COPD is defined by the Global Initiative for chronic Obstructive Lung Disease (GOLD) as "a disease state characterized by airflow limitation that is not fully reversible, and that is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases" [3]. Cigarette smoking is by far the most important risk factor for COPD. However, only a susceptible minority ( 1520%) of tobacco smokers develops clinically significant COPD, suggesting that genetic factors (such as the rare hereditary deficiency of 1-antitrypsin) must modify each individual's risk. Therefore, although the major environmental risk factor for COPD tobacco smoke is well known since many years, the cellular and molecular mechanisms that are involved in the pathogenesis of COPD have not yet been fully elucidated. In COPD, there is a chronic inflammation of the small airways and the lung parenchyma, leading to fixed narrowing of small airways and alveolar wall destruction (emphysema) [4]. Multiple studies of lung specimens, bronchial biopsies and bronchoalveolar lavage fluid of patients with COPD have demonstrated that this chronic inflammation is characterized by increased numbers of alveolar macrophages, neutrophils and lymphocytes [5]. Especially CD8+ T-lymphocytes are increased in the peripheral airways and lungs of smokers with COPD as compared with asymptomatic smokers with normal lung function [6,7]. Moreover, the extent of emphysema in smokers has been related to the number of CD3+ T-cells in the alveolar wall, and CD8+ T-lymphocytes appeared to be the predominant cells in the alveolar wall of emphysematous lungs [8,9]. One of the important functions of CD8+ T-cells is their cytolytic activity, inducing cell death by perforin mediated lysis and apoptosis by caspase activation [10]. These data suggest an important role of CD8+ T-lymphocytes in the pathogenesis of COPD and emphysema. Recently, Hogg et al. further characterized the nature of the small airway obstruction in patients with COPD of increasing severity [11]. Progression of COPD from mild disease (GOLD stage 1) to very severe COPD (GOLD stage 4) was associated with thickening of the airway wall and with an increased number of airways containing lymphocytes (not only CD8+ T-cells, but also CD4+ T-ce (...truncated)


This is a preview of a remote PDF: http://respiratory-research.com/content/pdf/1465-9921-6-147.pdf

An I D'hulst, Tania Maes, Ken R Bracke, Ingel K Demedts, Kurt G Tournoy, Guy F Joos, Guy G Brusselle. Cigarette smoke-induced pulmonary emphysema in scid-mice. Is the acquired immune system required?, Respiratory Research, 2005, pp. 147, 6, DOI: 10.1186/1465-9921-6-147