- To assess genetic predisposition to neutrophil-mediated lung injury via screening for a regulatory sequence mutation of the alphaPI gene.
- To assess the potential of antioxidants to prevent inflammatory inactivation of antiproteases.
- To assess the ability of antiproteases, alone and in combination with antioxidants, to modulate inflammatory cytokine production by lung cells.
A dominant feature of the inflammatory response in the majority of chronic and acute respiratory diseases is an influx on neutrophils to the lung where, via the release of destructive proteases and oxidants, they mediate the tissue injury which results in morbidity and death. Development of early-onset emphysema in individuals with congenital deficiency of the protease inhibitor, alpha1PI, first highlighted the importance of antiprotease defenses in protecting the lung against neutrophil mediated injury. Recent studies indicate that a newly identified mutation in the regulatory sequence of the alpha1PI gene may also confer susceptibility to the development of chronic pulmonary disease. Via genetic screening the project will determine the incidence of this novel mutation in European patient populations and assess whether this mutation might also contribute to individual variation in severity of chronic lung disease and in susceptibility to acute luna injury.
Given the central role of neutrophil proteases in mediating lung injury, measures to increase the antiprotease defenses of the lung are of considerable therapeutic interest. A significant problem in the development of effective antiprotease therapies is their susceptibility to oxidant and protease inactivation in the inflamed lung. However, if they can survive inactivation recent studies suggest that, in addition to protecting against direct protease injury, antiproteases may also act to reduce neutrophil influx. Antioxidants, in particular, appear to protect against antiprotease inactivation. Thus, the second aim of the project is to examine the newly-identified antiinflammatory potential of antiproteases and assess the ability of antioxidants to enhance these effects.
To achieve these objectives the network takes advantage of the participants' expertise in genetic screening, clinical evaluation, animal model systems, chemokine action, molecular biology and assessment of protease - antiprotease and oxidant-antioxidant interactions.