REGULATION OF AIRWAY LACTOPEROXIDASE HOST DEFENSE

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DESCRIPTION (Applicant's Abstract): Respiratory infection is a major cause of human morbidity and mortality in infants, the elderly, the immune-compromised and those on mechanical ventilators. The airway epithelium and submucosal glands provide the first defense against such infection by secreting several antibiotic substances. However, little is known regarding the several identified non-immunologic mucosal defenses. More knowledge of airway anti-infection defense will be valuable for designing prophylactic therapy for individuals predisposed to airway infection, e.g., in cystic fibrosis and bronchiectasis. The long-term goal of the proposed studies is to gain information about lactoperoxidase (LPO)-mediated non-immunologic defense in the airway. Recent work in this lab has shown that a significant amount of LPO is present in airway mucus, that LPO's substrates, thiocyanate (SCN-) and hydrogen peroxide (H2O2), are also present in the airway, that LPO is the major in vitro H2O2 scavenging activity in mucus, and that, in vivo, LPO catalytic activity is important for clearance of inhaled bacteria. Based on the above observations, the proposed experiments will test hypotheses regarding the regulation of the airway LPO system. The studies will use both differentiated airway epithelia at an air-liquid interface and submucosal gland cells in submerged cultures. Studies outlined in Specific Aim 1 will test the hypothesis that LPO synthesis or secretion is regulated by infection-related inflammatory stimuli and will study LPO's biosynthetic pathway. Specific Aim 2 will test the hypothesis that SCN- is carried into the airway lumen by a basolateral active transporter coupled to an apical anion channel and test whether this anion transport may be defective in cystic fibrosis. Specific Aim 3 will test the hypothesis that levels of the LPO substrate, H2O2, are also regulated by infection-related inflammatory stimuli and will identify the enzymatic source of H2O2. Understanding the regulatory mechanism of the LPO system will provide an opportunity for development of new prophylactic and therapeutic anti-infective agents. In addition, the studies may provide important insight into the pathophysiology of airway diseases characterized by chronic airway infection such as cystic fibrosis and bronchiectasis.