Platelet activating factor receptor: gateway for bacterial chronic airway infection in chronic obstructive pulmonary disease and potential therapeutic target

Abstract

The authors established that cigarette smoke increases airway epithelial platelet activating factor receptor (PAFr) expression and that PAFr is markedly up-regulated in the lungs of chronic obstructive pulmonary disease (COPD) patients. Crucially, PAFr is used by the two key bacterial species involved in chronic infection and acute exacerbations in COPD, that is, Streptococcus pneumoniae and Haemophilus influenzae, as a receptor for lung epithelial colonization. The cognate adhesin of PAFr, phosphorylcholine (ChoP), in the cell wall of these bacterial species may be a key effector that underpins host colonization. In this review, the authors evaluate the respective roles of PAFr and ChoP in the natural history of COPD and discuss the potential of the airway epithelial PAFr–bacterial ChoP interaction as a selective anti-infective target in COPD therapeutics.

Keywords:

• airway epithelium
• bacterial adhesion
• inhaled corticosteroids
• PAFr antagonist
• platelet activating factor receptor
• pneumococcal infections

Financial and competing interests disclosure

The authors were supported by NHMRC Centre of Research Excellence, University of Tasmania. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The global burden of chronic obstructive pulmonary disease (COPD) is increasing both in terms of mortality and morbidity. More than 3 million people die every year from COPD, making it the fourth leading cause of mortality worldwide.

• Smokers, in particular, are at significantly higher risk to develop COPD and the mortality is projected to increase by >30% by 2020, if the underlying risk factors, especially smoking, are not checked.

• Long-term exposure to tobacco smoke initiates a vicious cycle of airways and lung damage and remodeling, leading to progressive decline in lung function, chronic cough and frequent exacerbations.

• Chronic airway infection, mainly with Streptococcus pneumoniae and Haemophilus influenzae, is characteristic of COPD and is a major cause of morbidity and acute exacerbations (∼50–65%); it poses a challenge in managing patients. Our understanding regarding the mechanisms of colonization of these pathogens in COPD is still limited.

• The first step of bacterial pathogenesis is adhesion of bacteria to the host epithelial cells; both these key pathogens express phosphorylcholine that binds specifically to the platelet activating factor receptor (PAFr) potentially expressed on the airway epithelial cell surface. These are markedly increased in density in COPD, likely to be a cause of chronic colonization/invasion of host cells. Better understanding of host-associated factors, bacteria-associated factors, as well as the host–pathogen interactions are needed.

• In vitro and animal models have demonstrated a significant reduction in adhesion of S. pneumoniae and H. influenzae to epithelial cells by a PAFr antagonist. Therefore, blocking PAFr–bacteria interactions may prevent or reduce airway infections in COPD.

• Current treatment in COPD focuses on reducing the symptoms (dyspnea and chronic cough) and reducing exacerbations. A novel non-antibiotic therapy to treat infection would be welcome and would avoid the problem of antibiotic resistance among common pathogens.

• The challenge is to identify and validate PAFr antagonists that could be deliverable in inhaled form, are potent and specific to PAFr, are well tolerated in humans and synergistic with current treatment.

Notes