LAUSR

Polymorphonuclear neutrophils (PMN) figure prominently in host defense against infection and in non-infectious inflammation. Mobilized early in an inflammatory response, PMN mediate immediate cellular defense against microbes and orchestrate events that culminate in cessation of inflammation and restoration of homeostasis. Failure to terminate inflammation, due either to persistent stimulation or faulty downregulation, can fuel exuberant inflammation characteristic of many human diseases, including cystic fibrosis (CF). An autosomal recessive genetic disease caused by mutations in the cystic fibrosis conductance regulator (CFTR), CF affects multiple end-organs, with chronic neutrophilic inflammation in airways predominating the clinical picture. To match the diverse microbial challenges that they may encounter, PMN possess a variety of antimicrobial systems to slow or kill invading microorganisms confined in their phagosomes. Prominent among PMN defense systems is their ability to generate hypochlorous acid (HOCl), a potent microbicide, by reacting oxidants generated by the NADPH oxidase with myeloperoxidase (MPO) released from azurophilic granules in the presence of chloride (Cl-). Products of the MPO-H2O2-Cl system oxidize susceptible biomolecules and support a robust antimicrobial action against many, but not all, potential human pathogens. Underscoring that the MPO-H2O2-Cl system is integral to optimal host defense and proper regulation of inflammation, individuals with defects in any component of this system, as seen in chronic granulomatous disease or MPO deficiency, incur increased rates or severity of infection and signs of dysregulated inflammatory responses.