Fibronectin-Cleaving Activity in Bronchial Secretions of Patients with Cystic Fibrosis

Abstract

In cystic fibrosis, colonization of the airways with Pseudomonas aeruginosa follows colonization with Staphylococcus aureus and is related to accelerated deterioration of pulmonary function. Because P. aeruginosa adheres better to cell surfaces devoid of fibronectin, we searched for fibronectin-cleaving activity in bronchial secretions and saliva from 24 patients with cystic fibrosis who were followed up for 4.5 y and from two control groups. Proteolytic activity against 12sI-labeled fibronectin was continuously present in cysticfibrosis bronchial secretions; significantly higher fibronectin-cleaving activity was found in older vs. younger patients, in patients with advanced disease stages determined by a five-stage scoring system, and in those colonized with P. aeruginosa. The fibronectin-cleaving activity was due to neutrophil elastase and cathepsin G. Cystic fibrosis bronchial secretions had proteolytic activity against surface fibronectin of airway mucosal cells. Thus fibronectin-cleaving activity of bronchial secretions rather than of saliva may favor P. aeruginosa colonization of the upper respiratory tract in individuals with cystic fibrosis.Most individuals with cystic fibrosis who survive beyond the neonatal period die from respiratory failure, which is the consequence of chronic, progressively destructive bronchitis [1][2][3]. Clinical and pathological observations show extensive tissue destruction in the airways, which first causes obstruction and obliteration of small airways and thereafter destruction of the walls of large airways [4,5]. Early in the disease course the bacterial pathogens frequently found in the bronchial secretions are Staphylococcus aureus and Haemophilus influenzae. Later the airways of these subjects are invariably colonized with Pseudomonas aeruginosa, an event that initiates an acclerated deterioration of lung functions [3] as wellas an excessive systemic immune response [6]. These pathogens cannot be eliminated from the airways by antimicrobial therapy, and because the deleterious effect of P. aeruginosa infection in individuals with cystic fibrosis is well established, the identification of factors favoring colonization of the airways with P. aeruginosa is important. Coloniza-

α1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients

“…In the present study, high elastase activity levels in sputum were associated (5). HLE impairs the adaptive immunity by cleaving immunoglobulin G into F(ab) 2 and Fc fragments (6). The impaired host defence leads to increased numbers of bacteria harming the lung tissue (7).…”

“…Besides invading microorganisms that are the physiological target of elastase, a surplus of the enzyme damages host compounds and pulmonary structures, including cilia [4], elastin [5], fibronectin [6], surfactant proteins A and D [7,8], immunoglobulins [9] and cell surface receptors on neutrophils [10,11] and lymphocytes [12]. Such damage results in reduced mucociliary clearance [4] and impaired opsonophagocytosis [11].…”

Alpha1-antitrypsin deficiency alleles and the Taq-I G-->A allele in cystic fibrosis lung disease

“…The physiological role of this enzyme remains unclear, although it is likely to be important in the digestion of bacterial cell walls and the initiation and regulation of inflammation [23,24]. Free neutrophil elastase has many deleterious effects, including the destruction of lung elastin [23], cleavage of immunoglobulins [25] and fibronectin [26], a reduction in ciliary beat frequency [27] and the stimulation of mucus gland secretion [28].…”

Adherence of Pseudomonas aeruginosa to respiratory epithelium and the effect of leucocyte elastase

“…The spectrum of the human leucocyte elastase (HLE) substrates includes structural proteins such as collagen and elastin, and macromolecules such as proteoglycans (Havemann and Gramse, 1984). Fibronectin, a glycoprotein present in extracellular matrix and at the surface of epithelial cells, is also hydrolysed by HLE (McDonald et al, 1979;Suter et al, 1988). The proteolytic activity of saliva from severely ill patients has been shown to be significantly correlated with the increased adherence of P. aeruginosa to buccal cells in uitro, due to fibronectin degradation (Woods et al, 1980a(Woods et al, , 1983.…”