Unopposed Neutrophil Elastase in Bronchoalveolar Lavage from Transplant Recipients with Cystic Fibrosis

Abstract

Large numbers of neutrophils with unopposed neutrophil elastase (NE) proteolytic activity are found in lower respiratory tract secretions from most patients with advanced cystic fibrosis (CF). To determine whether antielastase defenses may be overwhelmed in epithelial lining fluid after lung transplantation, we measured NE activity (cleavage of the specific substrate, MeO-Suc-Ala-Ala-Pro-Val-pNA) in bronchoalveolar lavage fluids (BALF) obtained for surveillance or diagnostic purposes at various intervals (1 mo to 7 yr after transplantation) from 52 recipients who had undergone double or bilateral lung transplantation for end-stage CF. Unopposed NE activity was found in BALF from 14 recipients, most of whom also had >= 10(5) colony forming units (cfu) of Pseudomonas aeruginosa in BALF. Ten of the 14 recipients with unopposed NE in bronchoalveolar lavage (BAL) had developed obliterative bronchiolitis (OB), but only 8 of the 38 subjects without unopposed NE activity had OB (p = 0. 002; Fisher exact test). We conclude that antiprotease defenses in lower respiratory tract secretions of CF patients receiving lung allografts are sufficient in the majority of patients to prevent unopposed NE activity. However, the presence of unopposed NE activity in BAL from lung allografts of patients with CF is associated with progressive, irreversible OB and graft failure.

Neutrophil necrosis and annexin 1 degradation associated with airway inflammation in lung transplant recipients with cystic fibrosis

“…Large numbers of neutrophils become sequestered in the airways of patients with CF in association with chronic bacterial infection [1-3,14] and neutrophils can also appear in relatively large numbers in bronchoalveolar secretions of lung transplant recipients with CF as well as those of recipients with other transplant indications as a consequence of reperfusion injury, infection, or delayed allograft dysfunction [10,15,16]. We observed that intracellular intact annexin 1 was largely deficient in neutrophils from bronchial aspirates of lung transplant patients with CF and bacterial tracheobronchitis.…”

Effects of sinus surgery in patients with cystic fibrosis after lung transplantation: a 10-year experience

“…Patients with CF have a significantly higher risk of acquiring and harboring P. aeruginosa in the lung allograft compared with transplant recipients with other underlying diseases (2). P. aeruginosainduced inflammation may be associated with the occurrence of posttransplant bronchiolitis obliterans syndrome (BOS), leading to progressive, irreversible graft dysfunction and death (2,3).…”

Elevated Peptides in Lung Lavage Fluid Associated with Bronchiolitis Obliterans Syndrome

“…In fact, a peptide from human neutrophil elastase was found in pooled BOS samples. Neutrophilia has been associated with BOS [4]–[6], [11], [12] and generalized protease activity has been noted to increase in BOS along with a decrease in anti-protease activity [4], [12]. Our findings suggest that although other proteases are present, the neutrophil elastase is the predominant active protease.…”

“…In addition to a peribronchial infiltration of lymphocytes, neutrophilia also is a predominant finding in BOS [4]–[9]. These neutrophils release factors of the innate immune system, along with proteases [4], [10]–[12]. Despite the high incidence of BOS, the underlying pathogenesis remains unknown and no clinical biomarker has been found to predict its onset.…”