The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung

Abstract

Cystic fibrosis (CF) lung disease is an inherited condition with an incidence rate of approximately 1 in 2500 new born babies. CF is characterized as chronic infection of the lung which leads to inflammation of the airway. Sputum from CF patients contains elevated levels of neutrophils and subsequently elevated levels of neutrophil serine proteases. In a healthy individual these proteases aid in the phagocytic process by degrading microbial peptides and are kept in homeostatic balance by cognate antiproteases. Due to the heavy neutrophil burden associated with CF the high concentration of neutrophil derived proteases overwhelms cognate antiproteases. The general effects of this protease/antiprotease imbalance are impaired mucus clearance, increased and self-perpetuating inflammation, and impaired immune responses and tissue. To restore this balance antiproteases have been suggested as potential therapeutics or therapeutic targets. As such a number of both endogenous and synthetic antiproteases have been trialed with mixed success as therapeutics for CF lung disease.

Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism

“…2B). The WT-level growth of the SSVR mutants might argue against the importance of S1/S2 cleavages in HAE infections; however, we note that HAE are frequently collected from patients with underlying pulmonary diseases (e.g., chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis, α-1 antitrypsin deficiency), conditions associated with increased levels of mucus-associated proteases (40)(41)(42). Airway mucus-associated proteases are known to cleave SARS-CoV S proteins (43), and therefore we suggest that the SSVR mutant MERS-CoVs are similarly cleaved by extracellular proteases, making their infection resemble that of WT viruses at the point of entry into some HAE cells.…”

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis

“…Therefore, it may also be beneficial to design targeted interventions aimed at optimizing airway macrophage function in children with CF (56). Understanding the fate of extracellular NE is critical to correct the protease-antiprotease imbalance that characterizes CF airways (57). However, targeting NE may not suffice, because similar complex activation and compartmentalization may occur with other proteases, such as matrix metalloproteinases 2, 9, and 12, which originate from neutrophils and macrophages (46,(58)(59)(60).…”

Human airway trypsin-like protease, a serine protease involved in respiratory diseases

“…HAT in the upper respiratory tract. Previous investigations have demonstrated that serine proteases participate in the pathogenesis of inflammation, infection, and fibrotic processes in the airways and lung (5,10,17,28,31,42,49,62,113,141,144,150). We recently demonstrated the implication of matriptase in idiopathic pulmonary fibrosis (IPF) (10) through its activation of PAR-2.…”

“…The catalytic site of HAT (blue box) includes the catalytic triad His 227 , Asp 272 , and Ser 368 . Potential N-linked glycosylation sites, Asn-Asn-Ser and Asn-Pro-Ser at Asn144 and Asn 152 (diamond-headed arrows), are located on the boxed SEA domain. Four disulfide bonds are located in the extracellular region, at cysteine pairs 212/228, 337/353, and 364/393 in the catalytic region and at 173/292 between the noncatalytic region and the catalytic region.…”