title: Lung injury and degradation of extracellular matrix components by Aspergillus fumigatus serine proteinase.
abstract: 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 production. Nevertheless, evidence of direct pulmonary injury caused by the A. fumigatus serine proteinase is still lacking. The purpose of our work was: (1) to provide evidence for a pivotal role of A. fumigatus serine proteinase in producing lung injury in an animal model, and (2) to investigate the broadness of the substrate specificity of the proteinase towards extracellular matrix components. To achieve this aim, the proteinase from an A. fumigatus strain isolated from human airways was purified by a four-step procedure, including cation exchange and hydrophobic interaction. High-performance capillary electrophoresis, SDS-PAGE, determination of K(m) towards synthetic substrates, and inhibitory studies were used to further characterize the A. fumigatus serine proteinase. With reference to extracellular matrix components, the A. fumigatus serine proteinase was shown to degrade human lung elastin at a higher rate than an equimolar amount of human neutrophil elastase. Human lung collagen, type I and type III collagens, as well as fibronectin, were quickly digested by the A. fumigatus serine proteinase. Finally, mice intratracheally injected with the proteinase showed a significant degree of lower respiratory tract destruction. We conclude that the A. fumigatus serine proteinase is capable per se of hydrolyzing the major structural barriers of the lung.
authors.affiliation: Dipartimento di Biochimica, IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Iadarola
authors.forename: G
authors.initials: G
authors.lastname: Lungarella
authors.forename: P A
authors.initials: PA
authors.lastname: Martorana
authors.forename: S
authors.initials: S
authors.lastname: Viglio
authors.forename: M
authors.initials: M
authors.lastname: Guglielminetti
authors.forename: E
authors.initials: E
authors.lastname: Korzus
authors.forename: M
authors.initials: M
authors.lastname: Gorrini
authors.forename: E
authors.initials: E
authors.lastname: Cavarra
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.forename: J
authors.initials: J
authors.lastname: Travis
authors.forename: M
authors.initials: M
authors.lastname: Luisetti
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000201:enzymology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D019075:Electrophoresis, Capillary; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000187:drug effects*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012697:Serine Endopeptidases / Q000302:isolation & purification / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D003094:Collagen; D004549:Elastin; D012697:Serine Endopeptidases