Protein Carbohydrate Interactions in the Pathophysiology of Asthma Exacerbations

Investigator: John V. Fahy, MD
Sponsor: NIH National Heart, Lung, and Blood Institute

Location(s): United States


Airway mucus plugging is a life-threatening feature of acute asthma exacerbations, and no treatments can effectively hasten plug removal. Normal airway mucus gel is lightly cross-linked and fluid, whereas mucus casts in acute asthma are densely cross-linked and semi-solid. How these cross-links arise is poorly understood, but may involve as yet unidentified cross-linking proteins. We hypothesize that mucin polymers are cross-linked by endogenous multimeric lectins specific for galactosyl residues in their O-linked glycans. Our preliminary data includes evidence that: (i) galectin-3 (Gal-3) and intelectin-1 (ITLN-1) are multimeric lectins capable of cross-linking mucins; (ii) these proteins are present in the airway mucus of acute severe asthmatic and are protease sensitive; (iii) galactose, but not glucose, can compete with these lectins to decrease airway mucus cross-linking. We propose three Aims to further explore the mechanisms of mucus gel formation and turnover in health and in acute asthma and to identify the mucolytic potential of galactosyl sugars. In Aim 1 we will determine if Gal-3 and ITLN-1 increase mucin cross-linking, and if assembly of normal airway mucus gels requires these lectins. In Aim 2 we will test if galactosyl sugars competing off lectin the binding to mucins to decrease mucu elasticity. We will screen a library of glycomimetic carbohydrates for their ability to prevent mucin lectin binding and to act as mucolytics. We will also profile mucin glycans for the natural glcyan receptors for GAL-3 and ITLN-1. In Aim 3 we will focus on studies of airway mucus collected from asthmatic subjects in acute exacerbation. We will determine if GAL-3 and ITLN-1 are components of pathologic mucus in asthma exacerbations, explore the clinical and inflammatory correlates of different lectin profiles, and probe for lectin degradation products in mucus collected during asthma recovery. As in Aim 2, we will determine the effect of mucolytic sugars on the elastic modulus of asthmatic sputum, and we will explore if the natural glycan binding parnters for GAL-3 and ITLN1 are similar in asthma as in health. These studies address an important clinical problem with unmet therapeutic needs, use a multidisciplinary approach, and hold promise to reveal novel mucoltyic therapies for asthma.  This project aims to uncover mechanism of mucus gel formation in health and in acute asthma with a view toward the development of novel mucolytic therapies for acute asthma. Our preliminary studies have uncovered a novel mechanism of mucin cross-linking via multimeric lectins interacting with mucin glycans, a mechanism that provides a rationale for the use of specific carbohydrate structures as novel therapeutic agents for acute asthma.