The Neutrophil in Chronic Obstructive Pulmonary Disease. Too Little, Too Late or Too Much, Too Soon?

Abstract

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and has few effective therapies. It is characterized by anomalous and persistent inflammation, both local and systemic. Neutrophilic inflammation predominates in the COPD airway wall and lumen, but, despite the presence of abundant innate immune cells, the progressive clinical course of the disease is punctuated by recurrent infection-driven exacerbations. An extensive body of evidence (from cell culture to murine models and finally to the susceptibility of human patients with α1-antitrypsin deficiency to develop COPD) implicates neutrophil elastase and other neutrophil-derived proteases as key mediators of the tissue damage and relentless decline in lung function that occurs in this condition. In addition to the well recognized role of cytokines in modulating neutrophil function and survival, it has recently become apparent that hypoxia can influence neutrophil function, with impaired killing of pathogenic bacteria, enhanced release of proteases, and delayed apoptosis. This destructive neutrophil phenotype is predicted to be highly detrimental in the setting of the COPD microenvironment.

Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

“…The persistent presence of neutrophils in the lungs of COPD patients is thought to maintain inflammation through the release of active mediators such as proteolytic enzymes [5][6][7]. Paradoxically, neutrophils ).…”

“…We and others previously demonstrated that IL-22 protects and regenerates respiratory epithelial cells upon infection with influenza virus and limits secondary bacterial infections [4]. COPD is also characterised by high numbers of leukocytes, such as neutrophils in the lungs [5,6]. The accumulation and activation of neutrophils in COPD result in the excessive secretion of inflammatory molecules.…”

“…The accumulation and activation of neutrophils in COPD result in the excessive secretion of inflammatory molecules. Many studies suggest that neutrophil-derived proteases such as elastase and cathepsin G are key mediators of lung damage [5][6][7]. Neutrophil proteases degrade soluble mediators or matrix components and alter cell surface receptors [5].…”

“…Many studies suggest that neutrophil-derived proteases such as elastase and cathepsin G are key mediators of lung damage [5][6][7]. Neutrophil proteases degrade soluble mediators or matrix components and alter cell surface receptors [5]. Thus, we and others previously demonstrated that elastase and cathepsin G can deactivate receptors involved in host defence and inflammation, including the lipopolysaccharide (LPS) co-receptor CD14 [8,9] and various protease-activated receptors [10,11].…”

“…Defects in innate defence mechanisms have been documented in patients suffering from COPD, despite the abundance of innate immune cells such as neutrophils, which predominate in the airway wall and lumen of COPD patients [5,6]. Such immune defects may predispose COPD patients to viral or bacterial infections, which aggravate the disease.…”