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Cystic fibrosis is a genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator gene. Chronic inflammation and proteolysis lead to progressive damage of the bronchial wall. Extracellular matrix determines the structural organization and the mechanical properties of lung airways. It was thus examined in nine patients with cystic fibrosis (six bronchial biopsies and three lobectomies) in order to assess its level of alteration. The submucosal changes in matrix protein distribution were analyzed by immunochemistry and electron microscopy: the subepithelial basal lamina was thinned; an acellular collagen fiber layer composed of interstitial collagens (types I and III) subtended by tenascin and devoid of elastin-associated microfibrils was deposited beneath the basal lamina; this dense fibrous deposit generally formed a thick layer and could extend into the bronchial wall; the bronchial elastic framework lost arborescent distribution and appeared slender, packed, or lacunar; ultrastructural observation gave evidence for elastic and collagenic fiber lysis. Proteolytic activity is probably the major cause of matrix degradation. Fibrosis appears as a repair process rather than as an active fibrogenesis. The reversibility of extracellular matrix alterations is an important challenge and various interventions such as anti-inflammatory treatments can be targeted to halt or reverse this degradation process.
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INTRODUCTION |
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INTRODUCTION
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DISCUSSION
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Cystic fibrosis (CF) is the most common lethal genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The major causes of morbidity and mortality in CF are linked to the chronic inflammatory airway process, which leads to the progressive damage to small bronchioles and subsequently to proximal bronchi. The abnormalities in electrolytic transmembrane transport represent a primary pathophysiologic feature of the disease, but neither the genetic basis of CF nor the pathophysiology of the defective CFTR functions are sufficient to provide a unifying theory of the pathogenesis of the early and chronic inflammation (1).
The histopathologic and ultrastructural studies of CF airway epithelium failed to identify disease-specific cell abnormalities (2, 3), although changes in cell type distribution and ultrastructural organization have been described (2, 4): pseudostratification of ciliated columnar cells, marked goblet cell hyperplasia, epidermoid metaplasia, and submucosal glandular hyperplasia with dilated gland ducts. The submucosa is also the place of an inflammatory infiltrate with lymphocytes and plasma cells (5).
Evidence of early and severe airway inflammation in CF has been recently underlined (1, 6), particularly marked elevation in bronchoalveolar lavage (BAL) neutrophil count and elastase activity with an early protease-antiprotease imbalance (7, 8). Evidence of proteolytic activity in CF has been demonstrated, showing the presence of uninhibited neutrophil protease activity in BAL or sputum (9, 10) and urinary excretion of amino acids derived from cross-linked elastin and collagen, which are the markers of elastin and collagen degradation (9, 11).
In asthma, chronic inflammatory process and elastase activity have also been noted. Significant alterations in extracellular matrix have been underlined, showing dense collagenic deposition beneath the basement membrane (12) and evidence of elastic degradation (13). Elastolysis and collagen deposition probably have a damaging effect on lung structure and mechanical properties leading to chronic airway obstruction.
At the present time, the pathologic outcomes of the chronic inflammatory and proteolytic processes on extracellular matrix in CF has not been specifically described. In this study, the bronchial basement membrane and the submucosa were analyzed by immunohistochemistry using antibodies against matrix proteins and by transmission electron microscopy in nine patients with CF and in three normal subjects as reference in order to determine the features of degradation and remodeling of airway extracellular matrix structure.
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INTRODUCTION
METHODS
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Subjects
A total of nine patients with CF were recruited according to the following conditions between July 1995 and July 1996. Six patients had
fiberoptic bronchoscopy with lavage and biopsy. Five of them participated in a therapeutic protocol of administration of aerosolized 
1-
antitrypsin, including bronchoscopy before and after the drug administration. Bronchial biopsies were obtained during the first endoscopy
carried out before drug administration. This study was approved by
the regional ethics committee, and patients or parents gave written informed consent. One patient had biopsy during the course of a diagnostic bronchoscopy and gave informed consent for biopsy. Each patient
was premedicated with nalbuphin (0.3 mg/kg or 10 mg as maximal
dose) and midazolam (0.3 mg/kg or 10 mg as maximal dose), rectally
administrated, and had local anesthesia with lidocaine. The bronchoscopy was performed using a flexible fiberoptic Pentax BF 10 or Olympus BF-P20D (Olympus, London, UK). The biopsies were made on
the subdivision of the right middle lobe bronchus. Three patients underwent surgical lobectomy because of repeated infectious complications with predominant localized bronchiectasia. The selected samples
involved proximal bronchi. Clinical details of the nine patients are
shown in Table 1.
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The same protocol of bronchoscopy and bronchial biopsies was applied to three young nonsmoking healthy volunteers who gave written informed consent. The protocol was approved by the regional ethics committee.
Immunohistochemistry
An indirect immunofluorescence method using matrix component markers and fluorescein isothiocyanate-conjugated immunoglobulins was applied to cryostat sections 5 µm thick of fresh frozen tissue. Rabbit polyclonal antibodies against human type I collagen, bovine type III procollagen, murine laminin, and human elastin were obtained from the Institut Pasteur (Lyon, France). Rabbit polyclonal antihuman tenascin antibodies (A 107) and murine monoclonal antihuman cellular fibronectin cell attachment site antibodies (clone II 3E3 A 002) were purchased from Telios Pharmaceuticals (San Diego, CA). For control reaction, the specific antibody was omitted in the first incubation medium composed of 1% BSA in PBS at pH 7.2. The specificity of the present matrix protein antibodies has been previously demonstrated on several human tissues including the skin, the liver, and the lung (14).
Electron Microscopy
The fiberoptic bronchial biopsies and the selected samples of bronchi obtained from surgical lobectomy were covered with 2% glutaraldehyde-0.1 M Na-Cacodylate/HCl at pH 7.4, cut into 1-mm3 pieces and fixed in the same fixative for 2 h at 4° C. After three washings (3 h) at 4° C in 0.2 M Na-Cacodylate/HCl at pH 7.4, the specimens were postfixed in 1% osmium tetroxide-0.15 M Na-Cacodylate/HCl at pH 7.4 for 1 h at 4° C, dehydrated in graded ethanols, and flat-embedded in epon. Areas showing well preserved bronchial epithelium were selected on semithin sections stained with methylene blue-azure II. Consecutive ultrathin sections were contrasted with methanolic uranyl acetate and lead citrate, and observed under a Philips CM 120 transmission electron microscope.
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Immunohistochemistry
The selected matrix markers involved: (1) the basal lamina labeled by its laminin component; (2) the interstitial matrix of the bronchial wall: collagens and glycoproteins; (3) the elastic framework.
(1) Laminin staining in normal bronchus was continuous and intense at the epithelioconnective interface and around vessels (Figure 1c). In eight of nine CF patients with CF, the subepithelial basal lamina was clearly labeled, but it appeared more slender than perivascular and periglandular basal lamina and more slender than controls (Figure 1a and b). In Patient 1, the absence of laminin staining coincided with the disappearance of epithelium (Table 2).
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(2) In normal bronchus, tenascin and fibronectin formed a thin and regular layer restricted to the subepithelial area (Figure 1f and i), whereas interstitial collagens (type I and III) constituted the matrix network of the bronchial wall (Figure 2d and h). In patients with CF, the constant interstitial feature was the development of a continuous matrix layer under the basal lamina, specifically composed of tenascin (Figure 1d and e), as well as type I collagen (Figure 2a to c) and procollagen type III (Figure 2e to g). The tenascin deposit was either well layered (Figure 1d) or focally to diffusely infiltrating (Figure 1e) the subjacent matrix. Type I collagen was a predominant component of this subepithelial layer and was generally superposed on the tenascin deposit (Figure 2a and b). In two of three surgical samples (Patients 1 and 2), densely organized type I collagen extended to the whole thickness of the bronchial wall (Figure 2c). Procollagen type III was a major component of the subepithelial connective layer, too, but it extended to the bronchial wall in all patients, with a lacunary or dense fibrillar aspect (Figure 2e to g). In all samples, cellular fibronectin staining was weak, with a distribution similar to collagen staining (Figure 1g and h).
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(3) The normal bronchial elastic framework was arborescent from the deep elastic fibers up to the thin subepithelial oxytalanic fibers arranged perpendicular to the basal lamina (Figure 2l). In patients with CF, the elastic framework had lost its arborescent distribution. Subepithelial oxytalanic fibers were not observed (Figure 2i). The elastic network appeared slender and lacunar (Figure 2j) and was horizontally packed in three patients (Patients 2, 8, and 9) (Figure 2k and Table 2).
Transmission Electron Microscopy
An ultrastructural study was performed in six patients (Table 1). The ciliated epithelium was well preserved and continuously underlined by the basal lamina in four of six patients. In three of these four, neutrophilic polymorphonuclear cells infiltrated the intercellular space enlarged by edema and cell fragments (Figure 3b). Epithelial cell alterations were observed in the two other patients: single cell necrosis with focal interruption of the subepithelial basal lamina in Patient 6 (Figure 3c), and widely spread necrosis of epithelial cells identified by their ciliary remnants and devoid of basal lamina in Patient 1 (Figure 3d). In the other patients, the basal lamina was continuous and thin but had lost its microfibrillar anchorage to the subjacent fibrillar matrix (Figure 4b) compared with the normal subjects (Figure 4a).
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A distinct matrix layer was clearly visualized under the basal lamina in the four patients with preserved basal lamina (Patients 3 to 6). It was composed of thin collagen fibrils entangled without preferential orientation and embedded in abundant interfibrillar material (Figure 4c and d). Elastin- associated microfibrils were absent or rare in this area. Such a matrix layer was present but less developed and infiltrated by polymorphic inflammatory cells in Patient 2, whereas a dense fibrosis composed of close bundles of parallel collagen fibers extended all over the bronchial submucosa in Patient 1 (Figure 3d and Table 2).
Altered collagen fibers appeared enlarged and twisted on longitudinal sections (Figure 5a and c), and swollen and star-shaped on cross section (Figure 5b). The normal close association in large bundles of parallel fibers (Figure 5d) was lost. Hallmarks of degradation in collagenic fibers were observed in the subepithelial matrix layer in two patients (Patients 2 and 4) (Figure 5a) and in the underlying matrix stroma in four patients (Patients 2 to 6) (Figure 5b and c). In Patients 1 (Figure 3d) and 5 (Figure 4b), such degradation signs were not observed. The normal elastic network is composed of microfibrillar bundles (oxytalanic fibers) anchored to the basal lamina (Figure 4a) and of deep elastic fibers with predominant amorphous elastin component (Figure 5d). In all cases, elastic fibers were modified: partial or complete lack of elastin associated microfibrils in the subepithelial area (Figure 4d) as well as lysed and fragmented elastic fibers in the matrix stroma in four patients (Patients 2 to 6) (Figure 5b). The two same cases without observed collagenic degradation were also devoid of elastic degradation. The distribution of these elementary lesions in patients are summarized in Table 2.
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DISCUSSION |
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INTRODUCTION
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This study focused on the matrix changes of the bronchial wall in CF emphasizing three main features: (1) the establishment of a collagenic fibrillar layer beneath the basal lamina, (2) the degradative process affecting elastic and collagen fibers in the submucosa, and (3) the thinning of the subepithelial basal lamina. Furthermore, these features were constantly observed in biopsy samples from young patients with notably altered lung function tests. They might be regarded as the active process leading either to endstage bronchial fibrotic damage with epithelial loss or to destructive inflammatory cell infiltration observed in lobectomy samples.
In CF, the subepithelial basal lamina was not thickened, either in the bronchial wall or the nasal polyps, in contrast with atopy (15). The imbalance between metalloproteinase type IV collagenase and its inhibitor and the presence of free gelatinolytic activity may result in a defective basement membrane organization (16). This feature could not be proven by such a qualitative study but was supported by the weak laminin staining and focal rupture of the basal lamina.
The development of a collagenic fibrillar layer beneath the basal lamina has some similarities with that described in asthma (12), with the presence of tenascin (17) and interstitial collagens (type I and III) appearing as an aggregate of thin periodic collagen fibers. Elastic network alterations are also observed in both pathologies where airway inflammatory infiltration is constant. Nevertheless, three main noticeable differences from asthma were: (1) the exclusive deposition of tenascin, a matrix glycoprotein known to be overexpressed along growing and hyperplastic or tumoral epithelia (18), and it underlines a subepithelial matrix remodeling process, suggesting wound repair with enhanced renewal of the epithelial cell layer; (2) the weakness of cellular fibronectin and the absence of fibroblasts and myofibroblasts, involved in fibrogenesis (21), do not support the prevalence of an extensive fibrogenic process; (3) the absence of elastin-associated microfibrils, the anchorage structures of the bronchial wall elastic network to the subepithelial basal lamina (24), suggests previous destruction without the consecutive neogenesis observed in asthma (25). Such a fibrillar remodeling of the epithelioconnective interface might be regarded as a long-term support for the bronchial epithelium preservation without preventing the definitive loss of the oxytalanic fibers involved in bronchial wall cohesiveness.
Proteolytic activity has been frequently demonstrated by the presence of uninhibited elastase activity (9), neutrophil type I collagenase activity (10), type IV collagenase (16) in BAL or sputum, and by the presence of markers of collagen and elastin degradation in urine (9). The histopathologic outcomes of this proteolytic process have only been observed in CF bronchia from three autopsy samples (9): elastin van Gieson's stains showed an altered lung elastin framework with fragmented fibers. The present study showed ultrastructural criteria of degradation of both elastic and collagen fibers in the submucosa (26). The degradative process can extend to the deep border of the subepithelial fibrillar layer. The consecutive shrinking and discontinuity of the peribronchial elastic network may be the major cause of the bronchial compliance defect and chronic airway obstruction also observed in asthma (13, 27, 28). In addition, elastase induces fibroblast migration through the extracellular matrix in a human airway model (29). It could, therefore, play an important role in the development of extensive fibrosis focally found in one patient with repeated bronchial exacerbations leading to lobectomy, or with diffuse distribution in some forms of end-stage disease (30).
The major cause of the observed lesions seems to be related to the proteolytic activity induced by chronic inflammatory and infectious processes. The responsibility of CFTR for
the modifications in normal immunologic functions of the airway epithelial cells (31) and for the activation or maintenance
of the early and chronic inflammatory airway process regardless of an active infection is suspected. The modifications in
cytokine expression usually described in CF bronchi are high
levels of proinflammatory cytokines such as TNF-, IL1
, IL8,
and IFN-
but low levels of IL10, anti-inflammatory cytokine,
which is normally produced by macrophages and airway epithelial cells (32, 33). Among cytokines, TNF- has been demonstrated to downregulate elastin gene expression (34) and to
induce the production of tenascin by culture bronchial cells (35)
and could, therefore, induce extracellular matrix changes. The
direct influence of CFTR dysfunction in matrix alterations and
collagen deposition remains unknown.
Collagen deposition has also been described in the pancreas and the liver, which are devoid of infectious processes. In the pancreas, interstitial fibrosis is supposed to follow acinar destruction and release of pancreatic enzymes (36). In the liver, portal fibrosis is related to proliferated bile ducts. Fibrosis does not reach the intralobular Disse-space. This collagen deposition with slight inflammatory infiltrate could be the result of toxic biliary substances (37). Besides, CFTR expression was demonstrated in human bile duct epithelial cells but not detected in hepatocytes (38), suggesting a potential responsibility in the development of subepithelial fibrosis.
Defining the early pathogenic course of the CF bronchial disease should make it possible to stage the extracellular matrix alterations. Reversing under various anti-inflammatory treatments is an important challenge for patients with advanced lesions; prevention must be the aim for patients in whom an early diagnosis is made.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Isabelle Durieu, Department of Internal Medicine, Centre Hospitalier Lyon-Sud, 69345 Pierre-Bénite, France.
(Received in original form July 22, 1997 and in revised form March 5, 1998).
Acknowledgments: The writers thank M. Raccurt and I. Berger for immunochemistry and electron microscopy technique; D. Hartmann, O. Azocar, and S. Guerret for providing antibodies to matrix proteins; G. Joly for overall expertise in electron microscopy and photography; and D. Louis for surgical samples.
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References |
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REFERENCES
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1. Khan, T. Z., J. S. Wagener, T. Bost, J. Martinez, F. J. Accurso, and D. W. H. Riches. 1995. Early pulmonary inflammation in infants with cystic fibrosis. Am. J. Respir. Crit. Care Med. 151: 1075-1082 [Abstract].
2. Oppenheimer, E. H.. 1981. Similarity of the tracheobronchial mucous glands and epithelium in infants with and without cystic fibrosis. Hum. Pathol. 12: 36-48 [Medline].
3. Carson, J. L., A. M. Collier, T. M. Gambling, M. R. Knowles, and R. C. Boucher. 1990. Ultrastructure of airway epithelial cell membranes among patients with cystic fibrosis. Hum. Pathol. 21: 640-647 [Medline].
4. Simel, D. L., J. P. Mastin, P. C. Pratt, C. L. Wisseman, J. D. Shelburne, and A. Spock. 1984. Scanning electron microscopic study of the airways in normal children and in patients with cystic fibrosis and other lung diseases. Pediatr. Pathol. 2: 47-64 [Medline].
5. Bedrossian, C. W. M., S. D. Greenberg, D. B. Singer, J. J. Hansen, and H. S. Rosenberg. 1976. The lung in cystic fibrosis: a quantitative study including prevalence of pathologic findings among different age group. Hum. Pathol. 7: 195-204 [Medline].
6. Konstan, M. W., K. A. Hilliard, T. M. Norvell, and M. Berger. 1994. Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am. J. Respir. Crit. Care Med. 150: 448-454 [Abstract].
7. Nakamura, H., K. Yoshimura, N. G. McElvaney, and R. G. Crystal. 1992. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J. Clin. Invest. 89: 1478-1484 .
8. Birrer, P., N. G. McElvaney, A. Rudeberg, C. W. Sommer, S. Liechti-Gallati, R. Kraemer, R. Hubbard, and R. G. Crystal. 1994. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am. J. Respir. Crit. Care Med. 150: 207-213 [Abstract].
9. Bruce, M. C., L. Poncz, J. Klinger, R. C. Stern, J. F. Thomashefski, and D. G. Dearborn. 1985. Biochemical and pathological evidence for proteolytic destruction of lung connective tissue in cystic fibrosis. Am. Rev. Respir. Dis. 132: 529-535 [Medline].
10. Power, C., C. M. O'Connor, D. McFarlane, S. O'Mahoney, K. Gaffney, J. Hayes, and M. X. Fitzgerald. 1994. Neutrophil collagenase in sputum from patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 150: 818-822 [Abstract].
11. Stone, P. J., M. W. Konstan, M. Berger, H. L. Dorkin, C. Franzblau, and G. L. Snider. 1995. Elastin and collagen degradation products in urine of patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 152: 157-162 [Abstract].
12. Roche, W. R., J. H. Williams, R. Beasley, and S. T. Holgate. 1989. Subepithelial fibrosis in the bronchi of asthmatics. Lancet i: 520-524 .
13. Bousquet, J., J. Y. Lacoste, P. Chanez, P. Vic, P. Godard, and F. B. Michel. 1996. Bronchial elastic fibers in normal subjects and asthmatic patients. Am. J. Respir. Crit. Care Med. 153: 1648-1654 [Abstract].
14. Takiya, C., S. Peyrol, J. F. Cordier, and J. A. Grimaud. 1983. Connective matrix organization in human pulmonary fibrosis: collagen polymorphism analysis in fibrotic deposit by immunohistological methods. Virchows Arch. B44:223-240.
15. Oppenheimer, E. H., and B. J. Rosenstein. 1979. Differential pathology of nasal polyps in cystic fibrosis and atopy. Lab. Invest. 40: 445-449 [Medline].
16. Delacourt, C., M. Le Bourgeois, M. P. D'Ortho, C. Doit, P. Scheinmann, J. Navarro, A. Harf, D. J. Hartmann, and C. Lafuma. 1995. Imbalance between 95 kDa type IV collagenase and tissue inhibitor of metalloproteinases in sputum of patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 152: 765-774 [Abstract].
17. Laitinen, A., A. Altraja, M. Linden, G. Ställenheim, P. Venge, L. Hakansson, I. Virtanen, and L. A. Laitinen. 1994. Treatment with inhaled budesonide and tenascin expression in bronchial mucosa of allergic asthmatics (abstract). Am. J. Respir. Crit. Care Med. 149: A942 .
18. Chiquet-Ehrismann, R., E. J. Mackie, C. A. Pearson, and T. Sakakura. 1986. Tenascin: an extracellular protein involved in tissue interactions during fetal development and oncogenesis. Cell 47: 131-139 [Medline].
19. Koch, M., B. Wehrle-Haller, S. Baumgartner, J. Spring, D. Brubacher, and M. Chiquet. 1991. Epithelial synthesis of tenascin at tips of growing bronchi and graded accumulation in basement membrane and mesenchyme. Exp. Cell Res. 194: 297-300 [Medline].
20. Chuong, C. M., and H. M. Chen. 1991. Enhanced expression of neural cell adhesion molecules and tenascin (cytotactin) during wound healing. Am. J. Pathol. 138: 427-440 [Abstract].
21. Rennard, S. I., G. W. Hunninghake, P. B. Bitterman, and R. G. Crystal. 1985. Production of fibronectin by the human alveolar macrophage: mechanism for the recruitment of fibroblasts to sites of tissue injury in interstitial lung disease. Proc. Natl. Acad. Sci. U.S.A. 78: 7147-7151 .
22. Sappino, A. P., W. Schurch, and G. Gabbiani. 1990. Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations. Lab. Invest. 63: 144-161 [Medline].
23. Peyrol, S., J. F. Cordier, and J. A. Grimaud. 1990. Intraalveolar fibrosis of idiopathic bronchiolitis obliterans-organizing pneumonia: cell-matrix patterns. Am. J. Pathol. 137: 155-170 [Abstract].
24. Cleary, E. G., and M. A. Gibson. 1983. Elastin associated microfibrils and microfibrillar proteins. Int. Rev. Connect. Tissue Res. 10: 197-209 .
25. Gindre, D., S. Peyrol, Y. Pacheco, J. A. Grimaud, and M. Perrin-Fayolle. 1995. Structural changes of the bronchial epithelio-connective interface in asthmatic patients (abstract). Am. J. Respir. Crit. Care Med. 151: A563 .
26. Emonard, H., S. Peyrol, and J. A. Grimaud. 1991. Tissue hyperfibrils are degraded forms of collagen fibrils: an ultrastructural study employing enzymatic treatments. J. Submicrosc. Cytol. Pathol 23: 427-430 [Medline].
27. Hance, A., and R. Crystal. 1975. The connective tissue of the lung. Am. Rev. Respir. Dis. 112: 657-711 [Medline].
28. Zapletal, A., K. J. Desmond, D. Demizio, and A. L. Coates. 1993. Lung recoil and the determination of airflow limitation in cystic fibrosis and asthma. Pediatr. Pulmonol. 15: 13-18 [Medline].
29. Chetty, A., P. Davis, and M. Infeld. 1995. Effect of elastase on the directional migration of lung fibroblasts within a three-dimensional collagen matrix. Exp. Lung Res 21: 889-899 [Medline].
30. Tomashefski, J. F., M. W. Konstan, M. C. Bruce, and C. R. Abramowski. 1989. The pathologic characteristics of interstitial pneumonia in cystic fibrosis. Am. J. Clin. Pathol 91: 522-530 [Medline].
31. Rennard, S. I., D. J. Romberger, J. H. Sisson, S. G. Von Essen, I. Rubinstein, R. A. Robbins, and J. R. Spurzen. 1994. Airway epithelial cells: functional role in airway disease. Am. J. Respir. Crit. Care Med. 150: S27-S30 .
32. Bonfield, T. L., J. R. Panuska, M. W. Konstan, K. A. Hilliard, J. B. Hilliard, H. Ghnaim, and M. Berger. 1995. Inflammatory cytokines in cystic fibrosis lungs. Am. J. Respir. Crit. Care Med. 152: 2111-2118 [Abstract].
33. Bonfield, T. L., M. W. Konstan, P. Burnfeind, J. R. Panuska, J. B. Hilliard, and M. Berger. 1995. Normal bronchial epithelial cells constitutively produce the anti-inflammatory cytokine interleukin-10, which is downregulated in cystic fibrosis. Am. J. Respir. Cell Mol. Biol. 13: 257-261 [Abstract].
34.
Kähäri, V. M.,
Y. Q. Chen,
M. M. Bashir,
J. Rosenbloom, and
J. Uitto.
1992.
Tumor necrosis factor- down-regulates human elastin gene expression.
J. Biol. Chem.
267:
26134-26141
35. Harkonen, E., I. Virtanen, A. Linnala, L. L. Laitinen, and V. L. Kinnula. 1995. Modulation of fibronectin and tenascin production in human bronchial epithelial cells by inflammatory cytokines in vitro. Am. J. Respir. Cell Mol. Biol. 13: 109-115 [Abstract].
36. Oppenheimer, E. H., and J. R. Esterly. 1973. Cystic fibrosis of the pancreas: morphologic findings in infants with and without pancreatic lesions. Archiv. Pathol. 96: 149-154 .
37. Linblad, A., R. Hultcrantz, and B. Strandvik. 1992. Bile-duct destruction and collagen deposition: a prominent ultrastructural feature of the liver in cystic fibrosis. Hepatology 16: 372-381 [Medline].
38. Cohn, J. A., T. V. Strong, M. R. Picciotto, A. C. Nairn, F. S. Collins, and J. G. Fitz. 1993. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Gastroenterology 105: 1857-1864 [Medline].
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I. Durieu, C. Amsellem, C. Paulin, M.-T. Chambe, J. Bienvenu, G. Bellon, and Y Pacheco Fas and Fas ligand expression in cystic fibrosis airway epithelium Thorax, December 1, 1999; 54(12): 1093 - 1098. [Abstract] [Full Text]
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