Alpha-1 Antitrypsin Reduces Severity of Pseudomonas Pneumonia in Mice and Inhibits Epithelial Barrier Disruption and Pseudomonas Invasion of Respiratory Epithelial Cells

Abstract

Nosocomial pneumonia (NP) is the third most common hospital-acquired infection and the leading cause of death due to hospital-acquired infection in the US. During pneumonia and non-pneumonia severe illness, respiratory tract secretions become enriched with the serine protease neutrophil elastase (NE). Several NE activities promote onset and severity of NP. NE in the airways causes proteolytic tissue damage, augments inflammation, may promote invasion of respiratory epithelium by bacteria, and disrupts respiratory epithelial barrier function. These NE activities culminate in enhanced bacterial replication, impaired gas exchange, fluid intrusion into the airways, and loss of bacterial containment that can result in bacteremia. Therefore, neutralizing NE activity may reduce the frequency and severity of NP. We evaluated human alpha-1 antitrypsin (AAT), the prototype endogenous NE inhibitor, as a suppressor of bacterial pneumonia and pneumonia-related pathogenesis. In AAT+/+ transgenic mice that express human AAT in lungs, mortality due to Pseudomonas aeruginosa (P.aer) pneumonia was reduced 90% compared to non-transgenic control animals. Exogenous human AAT given to non-transgenic mice also significantly reduced P.aer pneumonia mortality. P.aer-infected AAT+/+ mice demonstrated reduced lung tissue damage, decreased bacterial concentrations in lungs and blood, and diminished circulating cytokine concentrations compared to infected non-transgenic mice. In vitro, AAT suppressed P.aer internalization into respiratory epithelial cells and inhibited NE or P.aer-induced disruption of epithelial cell barrier function. The beneficial effects of human AAT in murine P.aer pneumonia raise the possibility of AAT use as a prophylactic treatment for NP in humans, and suggest a role for AAT as an innate immune mediator.

The Role of Neutrophil Elastase Inhibitors in Lung Diseases

“…In the transgenic a1-AT þ/þ mice strain expressing this protein, mortality due to pneumonia caused by Pseudomonas aeruginosa (PA) was reduced by 90% compared with that in nontransgenic mice. 21 Infected mice had reduced lung tissue inflammation and damage, as well as decreased bacterial load. Similarly, EPI-hNE4 (depelestat; Debiopharm S.…”

Host-pathogen interplay in the respiratory environment of cystic fibrosis

“…Neutrophils release large amounts of elastase following activation, which is normally neutralized by alpha 1 anti-trypsin (AAT). AAT has been shown to significantly reduce airway disease in mice infected with P. aeruginosa pneumonia [101]. Human recombinant AAT (rAAT) is currently under investigation in patients with CF [102].…”

Alpha-1-anti-trypsin-Fc fusion protein ameliorates gouty arthritis by reducing release and extracellular processing of IL-1β and by the induction of endogenous IL-1Ra

“…Mice transgenic for human AAT (AAT-tg), which is driven by the surfactin C promoter for selective expression in type-2 lung epithelium,16 have low circulating levels of human AAT but are nevertheless protected in models of multiple sclerosis23 and Pseudomonas pneumonia 24. Here we demonstrated that human AAT-tg mice were also protected against joint inflammation induced by local MSU/C16.0 injection.…”