On airway host defence during allergic inflammation

Abstract: Asthma is a chronic inflammatory disease of the airways, affecting and disablingapproximately 300 million people worldwide. The inflammatory profile ischaracterized by infiltration of eosinophils, which are a rich source of factors thatare implicated in tissue remodeling. The chronic inflammatory response and theremodeled phenotype create a hospitable environment for secondary bacterialinfections. In recent years, systemic infections caused by Streptococcuspneumoniae in asthmatics have received global attention. The risk of acquiringpneumonia in patients suffering from asthma is 2-10 fold increased as compared tohealthy individuals. The cause is not known and in this thesis we hypothesized thatthe dysregulated allergic response may impair innate host defenses. Themechanisms being investigated may help to explain how the prolonged anddysregulated inflammatory response increases the vulnerability of asthmatics toinvasive pneumococcal disease. Initially, the regulation of chemokines, inparticular eotaxins, by mast cell proteases was investigated. From this study, wewere able to map the region of eotaxin-3/CCL26 that harbors antimicrobial(COOH-terminal) and anti-endotoxin (NH2-terminal) activity followingproteolytic cleavage with mast cell chymase and tryptase, respectively. However,the receptor activating properties (NH2-terminal) were lost. In a separate study, theanti-endotoxin fragment derived from CCL26 conferred therapeutic benefits in amouse model of LPS-induced inflammation. Furthermore, the interaction ofchemokines, particularly Th-2 chemokines, with osteopontin (OPN) wasinvestigated. OPN is an anionic glycoprotein that is upregulated in asthma and itsexpression increases with the severity of asthma. OPN bound to the COOHterminalof chemokines and completely abolished their antimicrobial activitywithout affecting their NH2-terminal localized functions, including LPSneutralizationand receptor activating properties. To ascertain if whether theeffects of OPN are generic or specific for Th-2 chemokines, we investigated itsinteraction with the classical antimicrobial peptides that are constitutivelyexpressed and upregulated during COPD. Interestingly, OPN bound andneutralized their antimicrobial activity but did not interfere with the muraminidaseactivity and protease inhibitory function of lysozyme and secretory leukocyteprotease inhibitor (SLPI), respectively. These studies suggest that chemokines andantimicrobial peptides can serve as host defense peptides but their actions aremodulated by mast cell proteases and OPN. Therefore, there is an urgent need forstudies focusing on modification of antimicrobial peptides to become resistant toproteolytic cleavage, altered pH and various salt conditions. Also, the elucidationof the novel roles of OPN during allergic inflammation could present potentialpharmaceutical targets. Taken together, this thesis explains several mechanismsthat impair innate host defenses during allergic inflammation.