Low Levels of Tissue Inhibitors of Metalloproteinases With a High Matrix Metalloproteinase-9/Tissue Inhibitor of Metalloproteinase-1 Ratio Are Present in Tracheal Aspirate Fluids of Infants Who Develop Chronic Lung Disease

Ekekezie, Ikechukwu I; Thibeault, Donald W.; Simon, Stephen D.; Norberg, Michael; Merrill, Jeffrey D.; Ballard, Roberta A.; Ballard, Philip L.; Truog, William E.

doi:10.1542/peds.113.6.1709

Cited by 79 publications

(66 citation statements)

References 23 publications

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“…MMP9 knockout mice showed increased survival and less important modifications of lung structure after hyperoxia exposure compared to wild-type animals (15). Furthermore, MMP9/TIMP1 ratio has been shown to be elevated in tracheal aspirates of preterm infants who developed BPD (16,17). In our experiments, changes in MMP9 protein expression were synergistic with changes in other genes and proteins of the same pathway.…”

Section: Discussionsupporting

confidence: 53%

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

et al. 2015

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Background: Preterm infants having immature lungs often require respiratory support, potentially leading to bronchopulmonary dysplasia (BPD). Conventional BPD rodent models based on mechanical ventilation (MV) present outcome measured at the end of the ventilation period. A reversible intubation and ventilation model in newborn rats recently allowed discovering that different sets of genes modified their expression related to time after MV. In a newborn rat model, the expression profile 48 h after MV was analyzed with gene arrays to detect potentially interesting candidates with an impact on BPD development. Methods: Rat pups were injected P4-5 with 2 mg/kg lipopolysaccharide (LPS). One day later, MV with 21 or 60% oxygen was applied during 6 h. Animals were sacrified 48 h after end of ventilation. Affymetrix gene arrays assessed the total gene expression profile in lung tissue. results: In fully treated animals (LPS + MV + 60% O 2 ) vs. controls, 271 genes changed expression significantly. All modified genes could be classified in six pathways: tissue remodeling/ wound repair, immune system and inflammatory response, hematopoiesis, vasodilatation, and oxidative stress. Major alterations were found in the MMP and complement system. conclusion: MMPs and complement factors play a central role in several of the pathways identified and may represent interesting targets for BPD treatment/prevention.

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Section: Discussionsupporting

confidence: 53%

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

et al. 2015

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“…In children, TIMP-1 was increased in upper airway secretions of severe respiratory syncytial virus bronchiolitis and we speculate that TIMP-1 may be involved in inflammation leading to post bronchiolitic wheezing (28). Our results are very different from that seen in chronic lung disease of prematurity, where TIMP-1 is reduced early in the disease process (29). We propose that TIMP-1 excess may impair matrix turnover, leading to thickening of the EBM and airway remodeling, but may also have an immunomodulatory role that may well be crucial to its mode of action (10).…”

Section: Discussioncontrasting

confidence: 84%

Bronchoalveolar Lavage MMP-9 and TIMP-1 in Preschool Wheezers and Their Relationship to Persistent Wheeze

et al. 2008

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Atopic preschool children are more likely to develop persistent wheezing, which could be a consequence of early airway remodeling. Protease-antiprotease balance between MMP-9 and its cognate inhibitor TIMP-1 may be involved in this process. Our hypothesis was that atopic wheezing preschool children would have an imbalance of MMP-9 to TIMP-1 in bronchoalveolar lavage (BAL). BAL from 52 preschool wheezers was compared with 14 controls without wheeze. A subgroup completed an International Study of Asthma and Allergy in Childhood symptom questionnaire 2 y later. Molar ratios of MMP-9/TIMP-1 were higher in wheezy children (p Ͻ 0.001; median 4.0%, range 0 -8.7) than controls (0.6%, 0 -1.8), and showed an excess of TIMP-1 in the airway. BAL TIMP-1 was raised in children with persistent wheezing (p ϭ 0.028; 34.4 ng/mL, 9.1-93.1 compared with 10.6 ng/mL 6.1-18.6), as was serum levels of intercellular adhesion molecule-1 (p ϭ 0.027). The absolute concentration of TIMP-1 in the airway, rather than its molar ratio with MMP-9, was associated with persistent wheezing. The processes involved with airway remodeling are complex but excess TIMP-1 may impede matrix protein turnover and thereby contribute to persistent changes in airway structure and wheezing. W heezing is a common respiratory symptom among preschool children and while most outgrow their disease by mid childhood, some continue to wheeze and develop asthma. Atopic preschool children are more likely to have persistent wheezing associated with progressively reducing pulmonary function (1). The cause of this deteriorating pulmonary function is not known, but airway remodeling is implicated in the disease process, and has been found in school-aged children with asthma (2-6). Thickening of the epithelial basement membrane (EBM) is an age related event detectable by 3 y of age in severe recurrent wheezers (7,8).Although the inflammatory mechanisms underlying the remodeling process are not known, protease anti-protease balance is one factor that could lead to a disorder of matrix turnover (9). The matrixins are a family of proteases able to digest components of the extracellular matrix (ECM). Matrix metalloproteinase 9 (MMP-9) is the predominant matrixin in pulmonary tissue and is specifically inhibited by tissue inhibitor of metalloproteinase-1 (TIMP-1) in a 1:1 ratio (10). There are two opposing mechanisms by which MMP-9 and TIMP-1 could affect a remodeling process: First, an excess of active MMP-9 over TIMP-1 would allow unregulated destruction of the ECM leading to inflammation and wound repair (11). Second, an excess of TIMP-1 over MMP-9 would slow the turnover of the ECM, which may include thickening of the EBM.Although, there is accumulating evidence of a role for MMP-9 and TIMP-1 in adult asthma (11-16), there are conflicting results in children, in an age group where structural remodeling may actually be occurring (17,18). The aim of this study was to investigate MMP-9 and TIMP-1 in bronchoalveolar lavage (BAL) from preschool wheezers. Our hypotheses wer...

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“…Consistent with the assumption of a major role of MMP2 in septation process, lowered MMP2 activity appears as a characteristic feature of infants who develop BPD, during the initial, acute phase of the disease (46 -48). Elevated levels of the other gelatinase, MMP9, and high MMP9/TIMP1 ratio rather appear to be associated with the later, regenerative and chronic phases of the disease, and with fibrosis (48,49). A similar pattern was found in the extremely premature ventilated baboon (50).…”

Section: Other Ecm Components Ecm Remodeling and Interactions With mentioning

confidence: 64%

Control Mechanisms of Lung Alveolar Development and Their Disorders in Bronchopulmonary Dysplasia

et al. 2005

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Low Levels of Tissue Inhibitors of Metalloproteinases With a High Matrix Metalloproteinase-9/Tissue Inhibitor of Metalloproteinase-1 Ratio Are Present in Tracheal Aspirate Fluids of Infants Who Develop Chronic Lung Disease

Abstract: We conclude that low tracheal aspirate levels of TIMPs, with a high MMP-9/TIMP-1 ratio early in life, are associated with subsequent development of CLD.

Cited by 79 publications

References 23 publications

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation

Bronchoalveolar Lavage MMP-9 and TIMP-1 in Preschool Wheezers and Their Relationship to Persistent Wheeze

Control Mechanisms of Lung Alveolar Development and Their Disorders in Bronchopulmonary Dysplasia

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