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

Allergy and Inflammation Sciences, University of Southampton, Southampton, UK.
Pediatric Research (Impact Factor: 2.31). 03/2008; 64(2):194-9. DOI: 10.1203/PDR.0b013e318175dd2d
Source: PubMed


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 < 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 = 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 = 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.

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Available from: Michel Erlewyn-Lajeunesse, May 16, 2014
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    • "An imbalance between MMP-9 and TIMP-1 in induced sputum is associated with airway inflammation in asthma and chronic obstructive pulmonary disease.30 In the present study, we demonstrated for the first time that the levels of MMP-2, MMP-9 and MMP-13 are high relative to the levels of TIMP-1 and TIMP-2 in ongoing chronic inflammation of PAR and that MMP+ cells are correlated with mast cells in the early phase and with eosinophils in the late phase of the inflammatory reaction. "
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    ABSTRACT: Purpose: Allergic rhinitis (AR) and asthma share many characteristics, but structural changes are observed far less often in AR. Matrix metalloproteinases (MMPs) constitute a family of Zn-dependent endopeptidases that can decompose the extracellular matrix and basement membrane, and regulate cell infiltration. We analyzed the expression of MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), in allergic nasal mucosa after nasal allergen challenge (NAC) and determined their relationship to inflammatory cells. Methods: Nasal mucosa specimens were obtained at surgery performed for hypertrophied turbinates. We performed NAC with house dust mite (HDM) allergen disks and control disks, and took biopsies at 30 minutes, 6 hours, and 12 hours after NAC. Cells expressing MMP-2, MMP-9, MMP-13, TIMP-1, and TIMP-2, as well as eosinophils and mast cells, were analyzed immunohistochemically. The MMPs and TIMPs in allergic nasal mucosa were quantified using enzyme-linked immunosorbent assays. Results: At 30 minutes post-NAC, HDM-exposed nasal mucosa exhibited significantly more MMP-2+, MMP-9+, MMP-13+, TIMP-1+, and TIMP-2+ cells compared with control mucosa, and the numbers of MMP-9+ and TIMP-1+ cells correlated strongly with the number of mast cells. At 6 hours post-NAC, the numbers of MMP+ and TIMP+ cells did not differ significantly between HDM-exposed mucosa and control mucosa, but the ratios of MMP+ cells to TIMP+ cells were higher in HDM-exposed mucosa. At 12 hours post-NAC, the number of MMP-13+ cells tended to be higher in HDM-exposed mucosa and was strongly correlated with the number of eosinophils. Quantitatively, the levels of MMP-2 and MMP-13 were significantly higher than the MMP-9 level, and the TIMP-2 level was significantly higher than the TIMP-1 level in allergic nasal mucosa. Conclusions: We demonstrated increased expression of MMP-2, MMP-9, and MMP-13 in allergic nasal mucosa, high MMPs-to-TIMP-1 ratios, and a strong correlation between MMP-9 and mast cells and between MMP-13 and eosinophils. The imbalance between MMPs and TIMPs may contribute to the migration of inflammatory cells such as eosinophils and mast cells to the nasal mucosa of AR patients, suggesting a possible active role of MMPs in AR.
    Allergy, asthma & immunology research 07/2012; 4(4):231-9. DOI:10.4168/aair.2012.4.4.231 · 2.43 Impact Factor
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    ABSTRACT: The main goal of the paper was to assess the pattern of risk factors having an impact on the onset of early wheezing phenotypes in the birth cohort of 468 two-year olds and to investigate the severity of respiratory illness in the two-year olds in relation to both wheezing phenotypes, environmental tobacco smoke (ETS) and personal PM(2.5) exposure over pregnancy period (fine particulate matter). The secondary goal of the paper was to assess possible association of early persistent wheezing with the length of the baby at birth. Pregnant women were recruited from ambulatory prenatal clinics in the first and second trimester of pregnancy. Only women 18-35 years of age, who claimed to be non-smokers, with singleton pregnancies, without illicit drug use and HIV infection, free from chronic diseases were eligible for the study. In the statistical analysis of respiratory health of children multinomial logistic regression and zero-inflated Poisson regression models were used. Approximately one third of the children in the study sample experienced wheezing in the first 2 years of life and in about two third of cases (67%) the symptom developed already in the first year of life. The early wheezing was easily reversible and in about 70% of infants with wheezing the symptom receded in the second year of life. The adjusted relative risk ratio (RRR) of persistent wheezing increased with maternal atopy (RRR=3.05; 95%CI: 1.30-7.15), older siblings (RRR=3.05; 95%CI: 1.67-5.58) and prenatal ETS exposure (RRR=1.13; 95%CI: 1.04-1.23), but was inversely associated with the length of baby at birth (RRR=0.88; 95%CI: 0.76-1.01). The adjusted incidence risk ratios (IRR) of coughing, difficult breathing, runny/stuffy nose and pharyngitis/tonsillitis in wheezers were much higher than that observed among non-wheezers and significantly depended on prenatal PM(2.5) exposure, older siblings and maternal atopy. The study shows a clear inverse association between maternal age or maternal education and respiratory illnesses and calls for more research efforts aiming at the explanation of factors hidden behind proxy measures of quality of maternal care of babies. The data support the hypothesis that burden of respiratory symptoms in early childhood and possibly in later life may be programmed already in prenatal period when the respiratory system is completing its growth and maturation.
    Environment international 05/2009; 35(6):877-84. DOI:10.1016/j.envint.2009.03.004 · 5.56 Impact Factor
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    ABSTRACT: To describe a prospective classification for preschool wheezers according to temporal symptom pattern, and summarize findings relating to the management of viral wheeze and the use of short-term therapy for intermittent severe wheeze. Phenotypes defined from cohort studies should only be applied retrospectively at school age. A new classification that can be applied prospectively is discussed. The importance of early rhinovirus-induced wheezing as a risk factor for asthma has become apparent. However, there is no benefit from short-course oral steroids for acute viral wheeze in the majority of cases. There is conflicting evidence for the role of intermittent montelukast or inhaled steroids in the treatment of acute, intermittent wheeze. A link between reduced vitamin D intake during pregnancy and increased preschool wheeze in offspring has emerged, suggesting a potential role for vitamin D supplementation in primary prevention. On the basis of current evidence, a trial of bronchodilators is first-line therapy for viral wheeze, and maintenance montelukast or inhaled steroids may be considered in preschool wheezers with persistent symptoms and risk factors for future asthma. No disease-modifying therapies are available. New therapeutic options for preschool wheezing disorders are desperately needed.
    Current Opinion in Allergy and Clinical Immunology 05/2009; 9(2):141-5. DOI:10.1097/ACI.0b013e3283292230 · 3.57 Impact Factor
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