Abstract
Morbidity, mortality and economic burden caused by chronic obstructive pulmonary disease (COPD) is a significant global concern. Surprisingly, COPD is already the third leading cause of death worldwide, something that WHO had not predicted to occur until 2030. It is characterized by persistent respiratory symptoms and airway limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles of gases. Neutrophil is one of the key infiltrated innate immune cells in the lung during the pathogenesis of COPD. Neutrophils during pathogenic attack or injury decide to undergo for a suicidal death by releasing decondensed chromatin entangled with antimicrobial peptides to trap and ensnare pathogens. Casting neutrophil extracellular traps (NETs) has been widely demonstrated to be an effective mechanism against invading microorganisms thus controlling overwhelming infections. However, aberrant and massive NETs formation has been reported in several pulmonary diseases, including chronic obstructive pulmonary disease. Moreover, NETs can directly induce epithelial and endothelial cell death resulting in impairing pulmonary function and accelerating the progression of the disease. Therefore, understanding the regulatory mechanism of NET formation is the need of the hour in order to use NETs for beneficial purpose and controlling their involvement in disease exacerbation. For example, DNA neutralization of NET proteins using protease inhibitors and disintegration with recombinant human DNase would be helpful in controlling excess NETs. Targeting CXC chemokine receptor 2 (CXCR2) would also reduce neutrophilic inflammation, mucus production and neutrophil-proteinase mediated tissue destruction in lung. In this review, we discuss the interplay of NETs in the development and pathophysiology of COPD and how these NETs associated therapies could be leveraged to disrupt NETopathic inflammation as observed in COPD, for better management of the disease.
Highlights
Introduction nal affiliationsChronic obstructive pulmonary disease (COPD) is a progressive respiratory disease and is one of the leading cause of morbidities and mortality throughout the globe
In chronic obstructive pulmonary disease (COPD) patients, neutrophils are recruited to the airways and serine proteases such as Neutrophil Elastase (NE), Myeloperoxidases (MPO) are secreted by these cells which lead to alveolar tissue destruction [82,83]
Neutrophil apoptosis involves participation of two main pathways: The extrinsic pathway which occurs as a result of surface death receptors that bind to TNF-related apoptosis-inducing ligand (TRAIL), TNFα or Fas ligand (FasL) [104]
Summary
Noxious agents in the cigarette smoke injure the airway epithelium and activate the inflammatory cells to release a combination of proteases and inactivate several anti-proteases, resulting in protease and anti-protease imbalance [35,36]. Increased oxidative stress and protease to anti-protease imbalance are the other major phenomena involved in disease initiation and progression [37]. The hallmarks of smoking induced COPD include squamous cell metaplasia and goblet cell hyperplasia which causes increased cough and mucus secretion [38]. Mucociliary clearance is disrupted by the bronchi undergoing squamous metaplasia [39] and situation collectively leads the persistent airway inflammation
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