Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading global causes of morbidity and mortality. A hallmark of COPD is progressive airflow obstruction primarily caused by cigarette smoke (CS). CS exposure causes an imbalance favoring pro- over antioxidants (oxidative stress), leading to transcription factor activation and increased expression of inflammatory mediators and proteases. Different cell types, including macrophages, epithelial cells, neutrophils, and T lymphocytes, contribute to COPD pathophysiology. Alteration in cell functions results in the generation of an oxidative and inflammatory microenvironment, which contributes to disease progression. Current treatments include inhaled corticosteroids and bronchodilator therapy. However, these therapies do not effectively halt disease progression. Due to the complexity of its pathophysiology, and the risk of exacerbating symptoms with existing therapies, other specific and effective treatment options are required. Therapies directly or indirectly targeting the oxidative imbalance may be promising alternatives. This review briefly discusses COPD pathophysiology, and provides an update on the development and clinical testing of novel COPD treatments.

Keywords: COPD; chronic obstructive pulmonary dysfunction; current treatments; pathophysiology.

Figure 1

COPD phenotypes. Morphological differences exist between a normal lung and a lung with COPD. In addition, lungs with COPD can present two different characteristics: emphysema, which promotes alveolar destruction and consequent reduction in lung function, and bronchitis, which increases mucus production, narrowing airways and reducing air flow. Created with BioRender.com.

Figure 2

COPD pathophysiology. The toxins present in cigarette smoke lead to the recruitment of inflammatory cells and the release of inflammatory mediators. Macrophages release CXCL1, CXCL8, and LTB4, which attract neutrophils, and CCL2 and CXCL1, which attract monocytes. Neutrophils release ROS, enhancing inflammation and reductively inactivating α1 antitrypsin. They also release proteases, such as NE, leading to tissue damage. Epithelial cells and macrophages release CXCL9, CXCL10, CXCL11, and CXCL12, which attract Th1 and Tc1 lymphocytes. They also release IFN-γ, leading to alveolar destruction. Epithelial cells release CXCL8, recruiting and activating neutrophils, and TGF-β and FGF, recruiting fibroblasts that promote tissue fibrosis. Epithelial cells also attract CD8⁺ T cells believed to foster inflammation. Macrophages release TNF-α, IL-1β, and ROS, inducing MMP secretion by epithelial cells, macrophages, and neutrophils, causing tissue remodeling. CXCL1, chemokine (C-X-C motif) ligand 1; LTB4, leukotriene B4; CC, Chemokine (C-C motif); IFNγ, interferon gamma; TGF, transforming growth factor; FGF, fibroblast growth factor; TNF-α, tumor necrosis factor alpha; IL, interleukins; ROS, reactive oxygen species; MMPs, metalloproteinases. Created with BioRender.com.

Figure 3

Mechanism of action of drugs for the treatment of COPD. Pollutants and CS initiate an inflammatory response by attracting inflammatory cells and releasing inflammatory mediators. mAChR antagonists act as bronchodilators, promoting the release of CXCL8 and LTB4. AMPK and HMG-CoA reductase stimulants decrease inflammation. Inhibitors of inflammatory mediators, such as CXCL1, CXCL8, and CXCL5, act by decreasing chemoattraction of neutrophils and macrophages to the lung (underlying inflammation). Nrf2 stimulants increase the transcription of antioxidant genes, and block the release of pro-inflammatory mediators. Interleukin, EGFR, and TNF-α inhibitors antagonize the activation of MAPKs and PI3K, and attenuate the release of pro-inflammatory mediators, such as IL-6 and IL-1. ADRB2 agonists inhibit the release of inflammatory mediators, cause smooth muscle relaxation, and increase cAMP and cGMP. PDE4 inhibitors prevent cAMP degradation, increasing intracellular cAMP levels, leading to smooth muscle relaxation, and enhancing the bronchodilator effects of β-agonists. CS, cigarette smoke; mAChR, Muscarinic ACh receptors AMP, adenosine monophosphate, AMPK, AMP-activated protein kinase; ADRB2, beta-2-adrenergic receptor; CXCL, chemokine; IL, interleukin; ERK, extracellular signal-regulated kinases; GMP, guanosine monophosphate; HMG-CoA, 3-hydroxymethylglutaryl CoA reductase; LOX, lipoxygenase; LTB4, leukotriene B4; MMPs, matrix metalloproteinases; ADRB2, adrenoceptor Beta 2; NFkB, factor nuclear kappa B; Nrf2, nuclear factor erythroid 2-related factor 2; PDE4, phosphodiesterase 4, PI3K, phosphoinositide 3-kinases; PKC, protein kinase C; TNF-α, tumor necrosis factor alpha. Created with BioRender.com.

Figure 4

Research methodologies used to identify COPD treatments. Created with BioRender.com.