Elastin Structure, Biosynthesis, and Relation to Disease States

Sandberg, Lawrence B.; Soskel, Norman T.; Leslie, John G.

doi:10.1056/nejm198103053041004

Cited by 457 publications

(159 citation statements)

References 77 publications

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“…Although we have shown that fibronectin was present on the surface of epithelial cells of small airways of normal human lung tissue and that surface fibronectin disappeared after incubation of the tissue for I min with cystic fibrosis bronchial secretions, the correlation of adherence of P. aeruginosa to epithelial cell surfaces of the lower respiratory tract of patients with cystic fibrosis and absence of surface fibronectin remains to be established. That the proteolytic activity of neutrophil elastase and cathepsin G is not limited to fibronectin is certain: Elastase destroys the three major structural proteins of the lung and the airways, which are elastin, collagen, and proteoglycans [37,38]. Therefore, it is likely that these proteases produce extensive damage to airway epithelia.…”

Section: Discussionmentioning

confidence: 99%

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

Suter

Schaad²,

Morgenthaler³

et al. 1988

Journal of Infectious Diseases

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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-

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Section: Discussionmentioning

confidence: 99%

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

Suter

Schaad²,

Morgenthaler³

et al. 1988

Journal of Infectious Diseases

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“…Bronchial secretions from patients with CF con-tain numerous PMNs [2] that might contribute to airway damage by release of neutral proteases such as elastase, collagenase, cathepsin G, and others [4,5]. These enzymes are indeed able to destroy important structural proteins of the lung and its airways such as elastin, collagen, and proteoglycans [4,5] in vitro; in addition, they can inactivate important opsonins such as complement component C3 [6][7][8] and IgG and IgM immunoglobulins [9][10][11].…”

mentioning

confidence: 99%

“…These enzymes are indeed able to destroy important structural proteins of the lung and its airways such as elastin, collagen, and proteoglycans [4,5] in vitro; in addition, they can inactivate important opsonins such as complement component C3 [6][7][8] and IgG and IgM immunoglobulins [9][10][11]. It is also well established that they are released extracellularly during phagocytosis [12].…”

mentioning

confidence: 99%

Granulocyte Neutral Proteases and Pseudomonas Elastase as Possible Causes of Airway Damage in Patients with Cystic Fibrosis

Suter¹,

Schaad²,

Roux³

et al. 1984

Journal of Infectious Diseases

193

127

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We studied the possible role of granulocyte neutral proteases as mediators of airway destruction in patients with cystic fibrosis (CF) who were infected with Pseudomonas aeruginosa. We measured the enzymatic activities of bronchial secretions on purified radioactively labeled complement component three (C3), elastin, and a granulocyte elastase-specific substrate. Bronchial secretions from 18 patients with CF who were infected with P aeruginosa had a significantly higher mean value for C3 cleaving, elastolytic, and granulocyte elastase-like activity than did two control groups. High enzymatic activities were observed in patients with CF who have advanced bronchial disease (that had been determined by a clinical scoring system). Kinetics of proteolysis of radioactively labeled C3 and inhibition profiles of the activities of the three enzymatic activities studied suggest that they are mainly derived from granulocytes. In addition, 20 of 31 strains of P aeruginosa isolated from patients with CF inactivated purified o l-antiprotease in vitro. We postulate that granulocyte neutral proteases and P aeruginosa may act synergistically in the airways of patients with CF and may contribute to the destruction of elastin and inactivation of C3.Cystic fibrosis is a fatal hereditary disease, in which the leading cause of death is respiratory failure [I]. Patients with cystic fibrosis (CF) usually have a long history of purulent bronchitis leading to progressive destruction of small bronchioles and followed by involvement of the large airways [2]. The pathogens most frequently associated with these respiratory-tract infections are Staphylococcus aureus and Pseudomonas aeruginosa [2,3]. Clinical and pathological observations suggest that progressive airway destruction is accelerated during infections with P aeruginosa [2]. However, little information is available regarding the mechanisms involved in progressive bronchiolar and bronchial damage and the persistence of P aeruginosa in bronchial secretions.Bronchial secretions from patients with CF con- [4,5]. These enzymes are indeed able to destroy important structural proteins of the lung and its airways such as elastin, collagen, and proteoglycans [4,5] in vitro; in addition, they can inactivate important opsonins such as complement component C3 [6][7][8] and IgG and IgM immunoglobulins [9][10][11]. It is also well established that they are released extracellularly during phagocytosis [12]. Furthermore, P aeruginosa may secrete an elastase that destroys the two main inhibitors protecting the lung and its airways from the activity of PMN neutral proteases: al-antiprotease [13][14][15][16] and the bronchial mucosal proteinase inhibitor [17]. In addition, this bacterial elastase is also active on C3[18] and elastin [15].We therefore measured the enzymatic activities of bronchial secretions from patients with CF (who were infected with P aeruginosa) on purified human C3, bovine elastin, and a granulocyte elastase-specific substrate. Two groups of patients with bronchial secretions r...

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“…Elastin plays a key structural role in elastic tissues including arteries, skin, ligament, cartilage and tendons (Sandberg, Soskel et al 1981). As the dominant part of the elastic fiber, elastin confers resilience and elasticity essential to the function of these tissues.…”

Section: The Role Of Elastin In Vivomentioning

confidence: 99%