REGULATION OF INFLAMMATION BY PULMONARY COLLECTINS

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by applicant): Every day we breathe more than 7,000 liters of air, loaded with inorganic and organic particles and array of microbes. We all aspirate gram-positive and gram-negative microorganisms and their products every night during sleep yet, most normal humans rarely develop pneumonia. This is due to highly effective host defenses that have evolved to protect the lung. Understanding the mechanisms that keep the pulmonary immune system and the associated inflammatory response in check and yet prepared to respond quickly to potentially deadly or disease-causing materials is crucial in developing approaches to intervene in many pulmonary diseases. Pulmonary surfactant, a complex mixture of lipids and proteins within the alveolar compartment, is the first biological interface encountered by airborne microorganisms and inflammatory mediators and is uniquely situated to play a role in host defense and modulation of inflammation. Surfactant-associated proteins A and D (SP-A and SP-D) are both members of the C-type lectin superfamily and have been shown in recent in vivo studies to recognize a significant number of microorganisms and play a role in their clearance. On the other hand, they also appear to be important in regulating the degree of lung inflammation. In this proposal we will address the mechanisms that allow the pulmonary collectins to serve this dual discriminatory role in the lung. We hypothesize that in the resting alveolus SP-A and SP-D provide an anti-inflammatory screen to prevent casual activation of macrophages and other inflammatory cells. We will 1) determine the characteristics and mechanisms of the anti-inflammatory effect in vivo as well as 2) examine the effect of pulmonary collectins on inflammatory mediator production from macrophages and neutrophils. Next we will 3) examine the mechanisms by which lung collectins inhibit proinflammatory signal pathways, focusing on CD45 as a potential cell surface ligand that delivers anti-inflammatory signals to the cell via inhibition of the src family kinases (specifically Lyn) and preventing activation of P38MAPKinase. Finally we will determine the mechanisms involved in the role of SP-A and -D as "defense collagens," which is in complete contrast to their anti-inflammatory role. We will 4) show that attachment and aggregation of pulmonary collectins to particles or organisms such that they are presented to macrophages via their collagenous tails, leads to proinflammatory effects. We propose that caireticulin is important for this effect. The challenge remaining in acute lung injury is to unravel at the cellular and molecular level the complexities of the inflammatory response in order to target therapeutic interventions so that they will lessen the injurious consequences of inflammation while leaving the beneficial effects intact. Gaining an understanding of the mechanisms by which pulmonary collectins inhibit or stimulate lung inflammation will be critical to this process.