Animal models and mechanisms of tobacco smoke-induced chronic obstructive pulmonary disease (COPD)

Abstract

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, and its global health burden is increasing. COPD is characterized by emphysema, mucus hypersecretion, and persistent lung inflammation, and clinically by chronic airflow obstruction and symptoms of dyspnea, cough, and fatigue in patients. A cluster of pathologies including chronic bronchitis, emphysema, asthma, and cardiovascular disease in the form of hypertension and atherosclerosis variably coexist in COPD patients. Underlying causes for COPD include primarily tobacco use but may also be driven by exposure to air pollutants, biomass burning, and workplace related fumes and chemicals. While no single animal model might mimic all features of human COPD, a wide variety of published models have collectively helped to improve our understanding of disease processes involved in the genesis and persistence of COPD. In this review, the pathogenesis and associated risk factors of COPD are examined in different mammalian models of the disease. Each animal model included in this review is exclusively created by tobacco smoke (TS) exposure. As animal models continue to aid in defining the pathobiological mechanisms of and possible novel therapeutic interventions for COPD, the advantages and disadvantages of each animal model are discussed.

Keywords: animal models; chronic bronchitis; chronic obstructive pulmonary disease (COPD); emphysema; tobacco smoke.

Figure 1.. Potential pathways for the development of chronic obstructive pulmonary disease (COPD).

IP10, interferon-γ-induced protein 10; MIG, monokine induced by interferon-γ; I-TAC, interferon-inducible T cell α-chemoattractant; IL, interleukin; LTB₄, leukotriene B₄; NE, neutrophil elastase; MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of metalloproteinases; TGF-β, transforming growth factor beta; NF-κB, nuclear factor-kappa B; MAPK/AP-1, mitogen-activated protein kinase/activator protein-1.

Figure 2.. Potential mechanisms of endothelial cell injury in the development of chronic obstructive pulmonary disease (COPD).

In the inflammatory response of COPD induced by tobacco smoke, neutrophils migrate through the endothelium by trans-endothelial migration (TEM). Macrophage (MAC)-1 antigen, intracellular adhesion molecule (ICAM)-1 and endothelial-leucocyte adhesion molecule (ELAM)-1 on the surface of endothelial cells involved in TEM are upregulated. The expression of cell adhesion molecules also appears to be induced by endothelial dysfunction in COPD. Vascular endothelial growth factor (VEGF) is a regulator that increases endothelial permeability and leads to endothelial cell growth. By blockade of VEGF, the disappearance of lung tissue in emphysema appears to involve the progressive loss of capillary endothelial and alveolar epithelial cells through the process of apoptosis. On the other hand, VEGF concentration in induced sputum is significantly elevated in chronic bronchitis, which increases bronchial vascularity and leakage of plasma proteins resulting in airway narrowing in chronic bronchitis. In COPD, the synthesis and release of NO (nitric oxide) and prostacyclin are reduced, and the endothelin (ET)-1 is increased in pulmonary arteries. These changes of vasoactive mediators result in endothelial dysfunction with the subsequent proliferation of smooth muscle cell, which may contribute to intimal hyperplasia with the ensuing reduction of arterial lumen and increase pulmonary vascular resistance.

Figure 3.. Proposed mechanisms of NF-κB pathway in tobacco smoke (TS)-induced apoptosis in the lungs of rats.

Fas-ligand (FasL) mediated-apoptosis involves binding of ligands to the death receptor (Fas), which leads to activation of caspase 8. Both mitochondrial (caspase 9) and death receptor (caspase 8) pathways lead to activation of caspase 3, which ultimately result in cell death by apoptosis. Nuclear factor-kappa B (NF-κB) is the major anti-apoptosis transcription factor, which regulates the expression of anti-apoptotic genes, such as cellular inhibitors of apoptosis (c-IAP) and BCL-2 family members (e.g., BCL-2 and BCL-XL). It exists as a complex consisting of p50 and p65 (RelA) subunits. NF-κB is maintained in the cytoplasm by the inhibitory protein IκB, mainly IκBα, which is rapidly phosphorylated by IκB kinases (IKK) upon stimulation. Through suppression of IKK and induction of heat shock proteins (HSP70), TS inhibits NF-κB activity and downregulates NF-κB-dependent anti-apoptotic proteins, including members of BCL-2 and c-IAPs, leading to caspase activation, eventually inducing apoptosis. Reproduced from Zhong CY, Zhou YM, Pinkerton KE. NF-κB inhibition is involved in TS-induced apoptosis in the lungs of rats. Toxicology and Applied Pharmacology 2008; 230: 150–158.

Figure 4.. Possible mechanisms for the genesis of tobacco smoke (TS)-induced lung disease.

During smoking exposure inflammation, injury and remodeling are highly activated, while smoking cessation leads to a resolution in inflammation. Repeated TS exposure and cessation creates a renewed insult to the lungs, resulting in renewed inflammation that repeats and amplifies the injury process. Release of proteolytic enzymes during this injury further damages and remodels the lungs through a loss of elastic fibers, thus causing airspace enlargement of the alveoli. Intermittent exposure to TS promulgates these effects, leading to enhanced emphysema, which is one of the most common conditions that contributes to chronic obstructive pulmonary disease (COPD). Reproduced from Pinkerton KE, Poindexter ME. Harmful interruptions: Impact of smoking patterns on tumorigenesis and emphysema. Am J Respir Cell Mol Biol 2018;59:133–134.