Hyperoxia Induces Interstitial (Type I) and Increases Type IV Collagenase mRNA Expression and Increases Type I and IV Collagenolytic Activity in Newborn Rat Lung

Devaskar, Uday; Taylor, Wiley; Govindrajan, R.; Malicdem, Milagros; Heyman, Sarah; deMello, Daphne E.

doi:10.1159/000244093

Cited by 17 publications

(13 citation statements)

References 10 publications

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“…There are several reports of increased MMP-9 in the bronchoalveolar lavage fluid and in type II cells in adult rats after 85% hyperoxia exposure (33) and in the lungs of newborn rat pups (18,34). Our study confirms reports of increased MMP-9 with hyperoxia and further shows that deletion of MMP-9 improves the response to hyperoxia of the developing lung.…”

Section: Discussionsupporting

confidence: 89%

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Role of matrix metalloprotease-9 in hyperoxic injury in developing lung

Chetty

Cao²,

Severgnini³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chetty A, Cao G-J, Severgnini M, Simon A, Warburton R, Nielsen HC. Role of matrix metalloprotease-9 in hyperoxic injury in developing lung. Am J Physiol Lung Cell Mol Physiol 295: L584 -L592, 2008. First published July 25, 2008 doi:10.1152/ajplung.00441.2007.-Matrix metalloprotease-9 (MMP-9) is increased in lung injury following hyperoxia exposure in neonatal mice, in association with impaired alveolar development. We studied the role of MMP-9 in the mechanism of hyperoxia-induced functional and histological changes in neonatal mouse lung. Reduced alveolarization with remodeling of ECM is a major morbidity component of oxidant injury in developing lung. MMP-9 mediates oxidant injury in developing lung causing altered lung remodeling. Five-day-old neonatal wild-type (WT) and MMP-9 (Ϫ/Ϫ) mice were exposed to hyperoxia for 8 days. The lungs were inflation fixed, and sections were examined for morphometry. The mean linear intercept and alveolar counts were evaluated. Immunohistochemistry for MMP-9 and elastin was performed. MMP-2, MMP-9, type I collagen, and tropoelastin were measured by Western blot analysis. Lung quasistatic compliance was studied in anaesthetized mice. MMP-2 and MMP-9 were significantly increased in lungs of WT mice exposed to hyperoxia compared with controls. Immunohistochemistry showed an increase in MMP-9 in mesenchyme and alveolar epithelium of hyperoxic lungs. The lungs of hyperoxiaexposed WT mice had less gas exchange surface area and were less compliant compared with room air-exposed WT and hyperoxiaexposed MMP-9 (Ϫ/Ϫ) mice. Type I collagen and tropoelastin were increased in hyperoxia-exposed WT with aberrant elastin staining. These changes were ameliorated in hyperoxia-exposed MMP-9 (Ϫ/Ϫ) mice. MMP-9 plays an important role in the structural changes consequent to oxygen-induced lung injury. Blocking MMP-9 activity may lead to novel therapeutic approaches in preventing bronchopulmonary dysplasia. morphometry; elastin; bronchopulmonary dysplasia THE PATHOPHYSIOLOGICAL FEATURES of the newer forms of bronchopulmonary dysplasia (BPD) are characterized by increased airway responsiveness to direct stimuli, with evidence of minimal alveolarization, variable alveolar wall cellularity and fibrosis, and alveolar-capillary dysplasia (14). Alveolarization begins in the distal saccules of the lung in parallel with development of the alveolar capillary bed in infants born at 24 -28 wk of gestation (28). The major manifestation of hyperoxic lung injury in neonates is an interference with normal lung development, particularly alveolar development. In the new BPD, fewer and larger alveoli are present. Hyperoxiaexposed preterm baboons showed a complete arrest of alveolar septation with fewer and larger alveoli. Even though the normal signal for septation of the saccules is unknown, hyperoxia has been shown to delay alveolar development (14).Interactions between epithelial and mesodermal cells during lung development and repair from injury lead to characteristic morphological and functional changes in the n...

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Section: Discussionsupporting

confidence: 89%

“…We chose to focus on MMP-9 in this study because of reports showing elevated MMP-9 in bronchoalveolar lavage fluid collected from preterm infants who subsequently developed BPD (19) and in alveolar type II epithelial cells in adult rats after 85% hyperoxia exposure (33) and in the lungs of newborn rat pups after hyperoxic exposure (18,34).…”

Section: Discussionmentioning

confidence: 99%

Role of matrix metalloprotease-9 in hyperoxic injury in developing lung

Chetty

Cao²,

Severgnini³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Its bioavailability is regulated by both genetic and proteolytic mechanisms (26). Hyperoxia is known to activate proteases, including urokinase type plasminogen activator and matrix metalloproteinases (27)(28)(29), that are capable of cleaving and releasing extracellular matrix-bound proteins. Thus, increased mobilization of matrix-bound VEGF protein and their cleavage to more diffusable isoforms would lead to a rise in lavageable VEGF.…”

Section: Discussionmentioning

confidence: 99%

Endostatin and Vascular Endothelial Cell Growth Factor (VEGF) in Piglet Lungs: Effect of Inhaled Nitric Oxide and Hyperoxia

et al. 2003

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“…In experiments by Devaskar et al (18), Ͼ85% O 2 administered to rat pups between d 1 and d 6 increased type IV collagenase, however, this was largely during the saccular stage and into the early alveolarization stage before many events key to alveolar development. In a study from our laboratory (19), exposing rat pups to hyperoxia from birth caused an increase in pro-enzyme activity after 14 d of hyperoxia, as opposed to a maximum 10 d exposure in this study.…”

mentioning

confidence: 92%

“…Adult rats exposed to 85% O 2 had increased levels of MMP-2 and MMP-9 activities in both bronchoalveolar lavage fluid and type II cells (17). In newborn rat pups, 85% O 2 from d 1 to d 6 elevated type IV collagenase mRNA and activity (18), and we demonstrated that hyperoxia (Ͼ95% O 2 ) exposure from d 3 elevated MMP-2 pro-enzyme activity, in particular on d 17, in association with airway hyperplasia, histiocyte invasion, and edema (19). Hence hyperoxia-elevated MMP are associated with hyperoxia-induced lung pathology.…”

mentioning

confidence: 95%

Hyperoxia Decreases Matrix Metalloproteinase-9 and Increases Tissue Inhibitor of Matrix Metalloproteinase-1 Protein in the Newborn Rat Lung: Association with Arrested Alveolarization

2004

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ABTRACT Matrix metalloproteinases (MMP) are likely effectors of normal lung development, especially branching morphogenesis, angiogenesis, and extracellular matrix degradation. Because hyperoxia exposure (Ͼ95% O 2 ) from d 4 to 14 in newborn rat pups leads to arrest of alveolarization and mimics newborn chronic lung disease, we tested whether hyperoxia altered MMP-2 and -9 mRNA, protein, and enzymatic activity, and the mRNA and protein expression of the endogenous tissue inhibitor of MMP, TIMP-1. No changes due to hyperoxia exposure were observed in MMP-2 mRNA or pro-enzyme (72 kD) protein levels between d 6 and 14, although the overall protein mass and zymographic activity of the active (68 kD) enzyme were diminished (p Ͻ 0.05, ANOVA). However, hyperoxia significantly decreased levels of MMP-9 mRNA and pro-MMP-9 protein and diminished overall MMP-9 pro-enzyme activity.TIMP-1 mRNA was not elevated by hyperoxia until d 14, but protein levels were significantly (p Ͻ 0.001) elevated by hyperoxia from d 9 to 14. To estimate the potential of MMP inhibition to arrest alveolarization, administration of doxycycline (20 mg/ kg, twice daily by gavage), a pan-MMP proteolysis inhibitor, arrested lung alveolarization. We conclude that hyperoxia decreases MMP-9 mRNA, protein, and activity and elevates TIMP-1 protein, and these changes have the potential to contribute to the arrest of normal lung development. Lung alveoli are formed when immature saccules subdivide into functional gas-exchange units through formation of secondary septa (1, 2). The process of septation involves budding from the primary septum (saccular wall), formation of a double-capillary network, elongation of septa, coalescence of vessels to form a single capillary layer, and thinning of the septal walls (1, 2). Exposure of neonatal rats to hyperoxia during alveolarization interferes with the process of septation; alveolar number and internal surface area are decreased and the parenchymal airspace is enlarged (3-5). These parameters persist up to d 40 (6). Hyperoxia during the neonatal period also alters lung connective tissue, alters elastic fiber structure and concentration (7), and causes an inflammatory reaction characterized by interalveolar edema and proteinosis (3,5,8). Chronic inflammation of the neonatal lung leads to fibrosis and thickening of the septa (3, 5).MMP are a group of proteases that exist as pro-enzymes and are cleaved by other MMP to active forms that have several specialized functions, including extracellular matrix turnover. Some of their functions regulate processes associated with development, such as branching morphogenesis and angiogenesis as well as inflammatory processes and wound healing (9). MMP-2 and MMP-9, also called gelatinases-A and -B, respectively, cleave gelatin, type IV and V collagen, and elastin. Types IV, V, and VII collagens are associated with basement membranes (10). MMP-2 and MMP-9 exhibit increased gelatinolytic activities as the lung develops (11), and during the postnatal lung growth stage both MMP-2 and MM...

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Hyperoxia Induces Interstitial (Type I) and Increases Type IV Collagenase mRNA Expression and Increases Type I and IV Collagenolytic Activity in Newborn Rat Lung

Cited by 17 publications

References 10 publications

Role of matrix metalloprotease-9 in hyperoxic injury in developing lung

Role of matrix metalloprotease-9 in hyperoxic injury in developing lung

Endostatin and Vascular Endothelial Cell Growth Factor (VEGF) in Piglet Lungs: Effect of Inhaled Nitric Oxide and Hyperoxia

Hyperoxia Decreases Matrix Metalloproteinase-9 and Increases Tissue Inhibitor of Matrix Metalloproteinase-1 Protein in the Newborn Rat Lung: Association with Arrested Alveolarization

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