LUNG INJURY AND DEGRADATION OF EXTRACELLULAR-MATRIX COMPONENTS BY ASPERGILLUS-FUMIGATUS SERINE PROTEINASE

Aspergillus fumigatus produces a variety of extracellular proteinases that are believed to be virulence factors towards Aspergillus-related lung disease. Among Aspergillus proteinases, the serine proteinase is thought to play a major virulent role because of its widespread produc tion. Nevertheless, evidence of direct pulmonary injury caused by the A. fumigatus serine proteinase is still lacking. The purpose of our wo rk was: (1) to provide evidence for a pivotal role of A. fumigatus ser ine proteinase in producing lung injury in an animal model, and (2) to investigate the broadness of the substrate specificity of the protein ase towards extracellular matrix components. To achieve this aim, the proteinase from an A. fumigatus strain isolated from human airways was purified by a Sour-step procedure, including cation exchange and hydr ophobic interaction. High-performance capillary electrophoresis, SDS-P AGE, determination of K-m towards synthetic substrates, and inhibitory studies were used to further characterize the A. fumigatus serine pro teinase. With reference to extracellular matrix components, the A. fum igatus serine proteinase was shown 60 degrade human lung elastin at a higher rate than an equimolar amount of human neutrophil elastase. Hum an lung collagen, type I and type III collagens, as well as fibronecti n, were quickly digested by lire A. fumigatus serine proteinase. Final ly, mice intratracheally injected with the proteinase showed a signifi cant degree of lower respiratory tract destruction. We conclude that t he A. fumigatus serine proteinase is capable per se of hydrolyzing the major structural barriers of the lung.