Risk Factors for the Degradation of Lung Elastic Fibers in the Ventilated Neonate: Implications for Impaired Lung Development in Bronchopulmonary Dysplasia

Bruce, Margaret C.; Schuyler, Mark; Martin, Richard J.; Starcher, Barry; Tomashefski, Joseph F.; Wedig, Kathy E.

doi:10.1164/ajrccm/146.1.204

Cited by 80 publications

(34 citation statements)

References 3 publications

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“…An increase in alveolar size with fewer alveoli was found in postmortem specimens of surfactant-treated subjects by Husain et al (25) in which the MLI was significantly increased in BPD subjects compared with non-BPD. Hislop et al (23) and others (6,44) have shown that the lungs of preterm infants who received mechanical ventilation and oxy- . Quasistatic compliance (Qst) from anesthetized 13-day-old WT and MMP-9 (Ϫ/Ϫ) pups after 8 days of hyperoxia or room air exposure measured by forced oscillation technique.…”

Section: Discussionmentioning

confidence: 98%

“…Adult transgenic mice with MMP-9 overexpression in the alveolar macrophages developed enlarged alveoli with elastin breakdown (22). A paucity of elastic fibers in the wall of the alveoli was seen due to destruction of elastic fibers as a result of protease-antiprotease imbalance (6,8). We found in hyperoxia-exposed WT animals an increase in elastin in the body of the alveolar crests instead at their tips where elastin is normally located during septation.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 98%

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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“…Patients who develop BPD exhibit increased urinary desmosine levels (48), which have been attributed to increased elastin degradation due to proteolysis in association with infection and prolonged exposure of infants to hyperoxia (49). However, data presented here suggest that the increased desmosine levels may be due, at least in part, to an overactive cross-linking system in affected lungs, which could promote excessive cross-linking of elastin and collagen fibers, perhaps resulting in the accumulation of elastic fibers in peripheral lung tissue (9,10).…”

Section: Discussionmentioning

confidence: 99%

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Kumarasamy¹,

Schmitt²,

Nave³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. Objectives: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. Methods: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-b) was preemptively blocked in mice exposed to hyperoxia using TGFb-neutralizing antibodies. Lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxl1 promoters fused upstream of the firefly luciferase gene. Measurements and Main Results: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygeninjured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-b signaling drove aberrant lox, but not loxl1 or loxl2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. Conclusions: Lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-b signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD.

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“…In particular, they appear to alter alveolar formation, on the basis of morphometric studies of severe BPD (3,24). Alveolar formation is characterized by the multiplication of alveolar septa and the thinning of interalveolar walls, both of which require intense remodeling of the pulmonary extracellular matrix (4).…”

mentioning

confidence: 99%

Gelatinase activities in the airways of premature infants and development of bronchopulmonary dysplasia

Danan

Jarreau

Franco

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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2002.-Matrix-degrading metalloproteinases may play a role in the pathophysiology of bronchopulmonary dysplasia (BDP). We, therefore, evaluated correlations between gelatinase activities [metalloproteinase (MMP)-2 and MMP-9] or tissue inhibitor of metalloproteinase (TIMP)-1 levels present in the airways during the initial phase of hyaline membrane disease and the onset of BPD. Tracheal aspirates were obtained within 6 h of birth (day 0) from 64 intubated neonates with a gestational age Յ30 wk. Forty-five neonates were resampled on day 3 or 5. Total MMP-2 level measured by zymography fell with time, whereas total MMP-9 level and TIMP-1 levels, assayed by ELISA, increased; the MMP-9 increase correlated with the increase in airway inflammatory cell numbers. Among the parameters measured on day 0, 3, or 5, lower total MMP-2 level, lower birth weight, and higher fraction of inspired oxygen on day 0 were significantly and independently associated with the development of BPD. In conclusion, MMP-9 level and TIMP-1 levels increased after birth but are not linked to BPD outcome. In contrast, low MMP-2 level at birth is strongly associated with the development of BPD. metalloproteinase; lung development; newborn; extracellular matrix PREMATURE NEONATES WITH HYALINE membrane disease are at risk of developing bronchopulmonary dysplasia (BPD), as a sequel of both the disease and its treatment. The pathogenesis is unclear, but BPD is thought to result from damage to an immature lung. Mechanical ventilation, oxygen therapy, and airway inflammatory responses have all been implicated in the development of BPD (19). These insults appear to interfere with normal lung maturation, which is incomplete at birth. In particular, they appear to alter alveolar formation, on the basis of morphometric studies of severe BPD (3, 24). Alveolar formation is characterized by the multiplication of alveolar septa and the thinning of interalveolar walls, both of which require intense remodeling of the pulmonary extracellular matrix (4). Changes in matrix turnover have been experimentally linked to abnormal alveolar formation (20). The proteinase-antiproteinase balance in the lung is a key factor in harmonious matrix turnover. In particular, matrix metalloproteinases (MMPs), which can synergistically digest the major macromolecules of connective tissue matrices, have been implicated in physiological regulation of lung growth. The MMP gelatinase A (MMP-2) has been shown to play a role in the major collagen turnover that occurs during early postnatal rat lung growth (1, 2). We postulated that MMP-2 might also participate in human lung development and that inadequate MMP-2 levels in premature lungs exposed to insults could contribute to impaired lung growth and thus to BPD. We also postulated that MMPs may be secreted in excess during the inflammatory response associated with hyaline membrane disease and may, therefore, lead to tissue degradation. Gelatinase B (MMP-9) is the main MMP released by inflammatory cells such as neutrophils and alveolar macroph...

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Risk Factors for the Degradation of Lung Elastic Fibers in the Ventilated Neonate: Implications for Impaired Lung Development in Bronchopulmonary Dysplasia

Cited by 80 publications

References 3 publications

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

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

Lysyl Oxidase Activity Is Dysregulated during Impaired Alveolarization of Mouse and Human Lungs

Gelatinase activities in the airways of premature infants and development of bronchopulmonary dysplasia

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