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Matrix metalloproteinase gene polymorphisms and bronchopulmonary dysplasia: identification of MMP16 as a new player
Alice Hadchouel1, Fabrice Decobert, Marie-Laure Franco-Montoya
1INSERM, Unité 841, IMRB, équipe 06, Créteil, France.
Background:
Alveolarization requires coordinated extracellular matrix remodeling, a process in which matrix metalloproteinases (MMPs) play an important role. We postulated that polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia (BPD).
Methods And Findings:
Two hundred and eighty-four consecutive neonates with a gestational age of <28 weeks were included in this prospective study. Forty-five neonates developed BPD. Nine single-nucleotide polymorphisms (SNPs) were sought in the MMP2, MMP14 and MMP16 genes. After adjustment for birth weight and ethnic origin, the TT genotype of MMP16 C/T (rs2664352) and the GG genotype of MMP16 A/G (rs2664349) were found to protect from BPD. These genotypes were also associated with a smaller active fraction of MMP2 and with a 3-fold-lower MMP16 protein level in tracheal aspirates collected within 3 days after birth. Further evaluation of MMP16 expression during the course of normal human and rat lung development showed relatively low expression during the canalicular and saccular stages and a clear increase in both mRNA and protein levels during the alveolar stage. In two newborn rat models of arrested alveolarization the lung MMP16 mRNA level was less than 50% of normal.
Conclusions:
MMP16 may be involved in the development of lung alveoli. MMP16 polymorphisms appear to influence not only the pulmonary expression and function of MMP16 but also the risk of BPD in premature infants.
Insights
Genetic variations in MMP16 may protect premature infants from bronchopulmonary dysplasia (BPD). Specific MMP16 genotypes were linked to lower MMP16 protein levels and reduced risk of BPD development.
Area of Science:
- Pulmonary Medicine
- Genetics
- Neonatology
Background:
- Alveolarization, crucial for lung development, involves extracellular matrix remodeling mediated by matrix metalloproteinases (MMPs).
- Polymorphisms in MMP genes are hypothesized to influence MMP function in preterm infants, potentially affecting the risk of bronchopulmonary dysplasia (BPD).
Purpose of the Study:
- To investigate the association between single-nucleotide polymorphisms (SNPs) in MMP genes (MMP2, MMP14, MMP16) and the risk of developing BPD in preterm neonates.
- To explore the relationship between identified MMP gene polymorphisms, MMP expression, and protein levels in preterm infants.
Main Methods:
- Prospective study of 284 neonates with gestational age <28 weeks, including 45 who developed BPD.
- Genotyping for nine SNPs in MMP2, MMP14, and MMP16 genes.
- Measurement of MMP2 active fraction and MMP16 protein levels in tracheal aspirates; analysis of MMP16 expression in normal and arrested lung development models (human and rat).
Main Results:
- TT genotype of MMP16 C/T (rs2664352) and GG genotype of MMP16 A/G (rs2664349) were protective against BPD after adjusting for birth weight and ethnicity.
- These protective genotypes correlated with lower MMP2 active fraction and a threefold reduction in MMP16 protein levels in early tracheal aspirates.
- MMP16 expression is low during early lung development (canalicular, saccular stages) and increases during alveolarization; reduced MMP16 mRNA was observed in rat models of arrested alveolarization.
Conclusions:
- MMP16 plays a role in lung alveolar development.
- Polymorphisms in MMP16 influence pulmonary MMP16 expression and function, consequently affecting the risk of BPD in premature infants.
