Abstract
Bronchopulmonary dysplasia (BPD) can evolve in prematurely born infants who require mechanical ventilation because of hyaline membrane disease (HMD). The development of BPD can be divided in an acute, a regenerative, a transitional, and a chronic phase. During these different phases, extensive remodeling of the lung parenchyma with re-epithelialization of the alveoli and formation of fibrosis occurs. Matrix metalloproteinase-1 (MMP-1) is an enzyme that is involved in re-epithelialization processes, and dysregulation of MMP-1 activity contributes to fibrosis. Localization of MMP-1 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, were investigated in lung tissue obtained from infants who died during different phases of BPD development. In all studied cases (n = 50) type-II pneumocytes were found to be immunoreactive for MMP-1, TIMP-1, and TIMP-2. During the acute and regenerative phase of BPD, type-II pneumocytes re-epithelialize the injured alveoli. This may suggest that MMP-1 and its inhibitors, expressed by type-II pneumocytes, play a role in the re-epithelialization process after acute lung injury. Although MMP-1 staining intensity remained constant in type-II pneumocytes during BPD development, TIMP-1 increased during the chronic fibrotic phase. This relative elevation of TIMP-1 compared with MMP-1 is indicative for reduced collagenolytic activity by type-II pneumocytes in chronic BPD and may contribute to fibrosis. Fibrotic foci in chronic BPD contained fibroblasts immunoreactive for MMP-1 and TIMP-1 and -2. This may indicate that decreased collagen turnover by fibroblasts contributes to fibrosis in BPD development.
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Abbreviations
- BPD:
-
Bronchopulmonary dysplasia
- HMD:
-
Hyaline membrane disease
- MMP-1:
-
Matrix metalloproteinase-1
- MMPs:
-
Matrix metalloproteinases
- TIMP-1:
-
Tissue inhibitor of metalloproteinase-1
- TIMP-2:
-
Tissue inhibitor of metalloproteinase-2
- TIMPs:
-
Tissue inhibitors of metalloproteinases
- TGF-β:
-
Transforming growth factor-β
References
Avery ME, Mead J 1959 Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child 97: 517–523
Reynolds EO, Roberton NR, Wigglesworth JS 1968 Hyaline membrane disease, respiratory distress, and surfactant deficiency. Pediatrics 42: 758–768
Anderson WR 1990 Bronchopulmonary dysplasia: a correlative study by light, scanning, and transmission electron microscopy. Ultrastruct Pathol 14: 221–232
Gandy G, Jacobson W, Gairdner D 1970 Hyaline membrane disease. I. Cellular changes. Arch Dis Child 45: 289–310
de la Monte SM, Hutchins GM, Moore GW 1986 Respiratory epithelial cell necrosis is the earliest lesion of hyaline membrane disease of the newborn. Am J Pathol 123: 155–160
O'Brodovich HM, Mellins RB 1985 Bronchopulmonary dysplasia. Unresolved neonatal acute lung injury. Am Rev Respir Dis 132: 694–709
Northway WH Jr 1990 Bronchopulmonary dysplasia: then and now. Arch Dis Child 65: 1076–1081
Rosan RC 1975 Hyaline membrane disease and a related spectrum of neonatal pneumopathies. Perspect Pediatr Pathol 2: 15–60
Anderson WR, Engel RR 1983 Cardiopulmonary sequelae of reparative stages of bronchopulmonary dysplasia. Arch Pathol Lab Med 107: 603–608
Margraf LR, Paciga JE, Balis JU 1990 Surfactant-associated glycoproteins accumulate in alveolar cells and secretions during reparative stage of hyaline membrane disease. Hum Pathol 21: 392–396
Fukuda Y, Ferrans VJ, Schoenberger CI, Rennard SI, Crystal RG 1985 Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis. Am J Pathol 118: 452–475
Sinkin RA, Roberts M, LoMonaco MB, Sanders RJ, Metlay LA 1998 Fibronectin expression in bronchopulmonary dysplasia. Pediatr Dev Pathol 1: 494–502
O'Connor CM, FitzGerald MX 1994 Matrix metalloproteases and lung disease. Thorax 49: 602–609
Mauviel A 1993 Cytokine regulation of metalloproteinase gene expression. J Cell Biochem 53: 288–295
Shapiro SD, Senior RM 1999 Matrix metalloproteinases. Matrix degradation and more. Am J Respir Cell Mol Biol 20: 1100–1102
Sudbeck BD, Pilcher BK, Welgus HG, Parks WC 1997 Induction and repression of collagenase-1 by keratinocytes is controlled by distinct components of different extracellular matrix compartments. J Biol Chem 272: 22103–22110
Murphy G, Docherty AJ 1992 The matrix metalloproteinases and their inhibitors. Am J Respir Cell Mol Biol 7: 120–125
Pardo A, Ridge K, Uhal B, Sznajder JI, Selman M 1997 Lung alveolar epithelial cells synthesize interstitial collagenase and gelatinases A and B in vitro. Int J Biochem Cell Biol 29: 901–910
Planus E, Galiacy S, Matthay M, Laurent V, Gavrilovic J, Murphy G, Clerici C, Isabey D, Lafuma C, d'Ortho MP 1999 Role of collagenase in mediating in vitro alveolar epithelial wound repair. J Cell Sci 112: 243–252
Pilcher BK, Sudbeck BD, Dumin JA, Welgus HG, Parks WC 1998 Collagenase-1 and collagen in epidermal repair. Arch Dermatol Res 290: S37–46
Vaalamo M, Leivo T, Saarialho-Kere U 1999 Differential expression of tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4) in normal and aberrant wound healing. Hum Pathol 30: 795–802
Howard EW, Bullen EC, Banda MJ 1991 Preferential inhibition of 72- and 92-kDa gelatinases by tissue inhibitor of metalloproteinases-2. J Biol Chem 266: 13070–13075
Kossakowska AE, Edwards DR, Lee SS, Urbanski LS, Stabbler AL, Zhang CL, Phillips BW, Zhang Y, Urbanski SJ 1998 Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis. Am J Pathol 153: 1895–1902
Milani S, Herbst H, Schuppan D, Grappone C, Pellegrini G, Pinzani M, Casini A, Calabro A, Ciancio G, Stefanini F, et al 1994 Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol 144: 528–537
Selman M, Montano M, Ramos C, Chapela R 1986 Concentration, biosynthesis and degradation of collagen in idiopathic pulmonary fibrosis. Thorax 41: 355–359
Hayashi T, Stetler-Stevenson WG, Fleming MV, Fishback N, Koss MN, Liotta LA, Ferrans VJ, Travis WD 1996 Immunohistochemical study of metalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis. Am J Pathol 149: 1241–1256
Fukuda Y, Ishizaki M, Kudoh S, Kitaichi M, Yamanaka N 1998 Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases. Lab Invest 78: 687–698
Giedion A, Haefliger H, Dangel P 1973 Acute pulmonary X-ray changes in hyaline membrane disease treated with artificial ventilation and positive end-expiratory pressure (PEP). Pediatr Radiol 1: 145–152
Bancalari E, Abdenour GE, Feller R, Gannon J 1979 Bronchopulmonary dysplasia: clinical presentation. J Pediatr 95: 819–823
Laurent GJ 1987 Dynamic state of collagen: pathways of collagen degradation in vivo and their possible role in regulation of collagen mass. Am J Physiol 252: C1–9
Davidson JM 1990 Biochemistry and turnover of lung interstitium. Eur Respir J 3: 1048–1063
Adamson IY, Bowden DH 1974 The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen. Lab Invest 30: 35–42
Adamson IYR, Bowden DH 1975 Derivation of type-1 epithelium from type-2 cells in the developing rat lung. Lab Invest 32: 737–745
Kim HJ, Henke CA, Savik SK, Ingbar DH 1997 Integrin mediation of alveolar epithelial cell migration on fibronectin and type I collagen. Am J Physiol 273: L134–L141
Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC 1997 The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 137: 1445–1457
Burri PH 1997 Structural aspects of prenatal and postnatal development and growth of the lung. In: McDonald JA (ed) Lung Biology in Health and Disease. Marcel Dekker, New York, Basel, 1–35.
Toti P, Buonocore G, Tanganelli P, Catella AM, Palmeri ML, Vatti R, Seemayer TA 1997 Bronchopulmonary dysplasia of the premature baby: an immunohistochemical study. Pediatr Pulmonol 24: 22–28
Crouch EC, Mecham RP, Davila RM, Noguchi A 1997 Collagens and elastic fiber proteins in lung development. In: McDonald JA (ed) Lung Biology in Health and Disease. Marcel Dekker, New York, Basel, 327–364.
Rolland G, Xu J, Tanswell AK, Post M 1998 Ontogeny of extracellular matrix gene expression by rat lung cells at late fetal gestation. Biol Neonate 73: 112–120
Bonikos DS, Bensch KG, Northway WH Jr, Edwards DK 1976 Bronchopulmonary dysplasia: the pulmonary pathologic sequel of necrotizing bronchiolitis and pulmonary fibrosis. Hum Pathol 7: 643–666
Stocker JT 1986 Pathologic features of long-standing “healed” bronchopulmonary dysplasia: a study of 28 3- to 40-month-old infants. Hum Pathol 17: 943–961
Cherukupalli K, Larson JE, Rotschild A, Thurlbeck WM 1996 Biochemical, clinical, and morphologic studies on lungs of infants with bronchopulmonary dysplasia. Pediatr Pulmonol 22: 215–229
Bateman ED, Turner-Warwick M, Adelmann-Grill BC 1981 Immunohistochemical study of collagen types in human foetal lung and fibrotic lung disease. Thorax 36: 645–653
McAnulty RJ, Laurent GJ 1995 A Pathogenesis of lung fibrosis and potential new therapeutic strategies. Exp Nephrol 3: 96–107
Pardo A, Selman M, Ramirez R, Ramos C, Montano M, Stricklin G, Raghu G 1992 Production of collagenase and tissue inhibitor of metalloproteinases by fibroblasts derived from normal and fibrotic human lungs. Chest 102: 1085–1089
Edwards DR, Murphy G, Reynolds JJ, Whitham SE, Docherty AJ, Angel P, Heath JK 1987 Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J 6: 1899–1904
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We gratefully acknowledge Prof. Dr. R. Benner and Dr. V.H.J. van der Velden for critical reading of the manuscript.
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Dik, W., de Krijger, R., Bonekamp, L. et al. Localization and Potential Role of Matrix Metalloproteinase-1 and Tissue Inhibitors of Metalloproteinase-1 and -2 in Different Phases of Bronchopulmonary Dysplasia. Pediatr Res 50, 761–766 (2001). https://doi.org/10.1203/00006450-200112000-00022
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DOI: https://doi.org/10.1203/00006450-200112000-00022
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