Abstract
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 Two hundred and eighty-four consecutive neonates with a gestational age of Results 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 appears to 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.
Highlights
Despite major advances in the care of very-low-birth-weight (VLBW) infants, bronchopulmonary dysplasia (BPD) still affects 20 to 40% of survivors [1]
We recently observed a fourfold increase in MMP14 transcripts in lung fibroblasts during alveolarization [7], while mice lacking this enzyme have a reduced alveolar surface area and enlarged air spaces [8,9], this seems partly independent of the ability of MMP14 to activate MMP2 [9]
As we found a significant association with two single-nucleotide polymorphisms (SNPs) in the MMP16 gene, we further examined the expression of this enzyme during normal human and rat lung development, and in newborn rat models of arrested alveolar development
Summary
Despite major advances in the care of very-low-birth-weight (VLBW) infants, bronchopulmonary dysplasia (BPD) still affects 20 to 40% of survivors [1]. Alveolarization requires coordination of extracellular matrix remodeling with epithelial morphogenesis and capillary growth [3] This process involves matrix metalloproteinases (MMPs), which are classified into two major groups according to their subcellular localization: membrane-type MMPs (MT-MMPs) and secreted MMPs. Among secreted MMPs, MMP2 is known to play a key role in lung development and repair after injury. Among secreted MMPs, MMP2 is known to play a key role in lung development and repair after injury Mice lacking this proteinase show delayed alveolar development [4], and low MMP2 levels in tracheal effluent and plasma have been linked to an increased risk of BPD in infants [5,6]. MMP16 is known to have a splice variant, consisting of a soluble form lacking the transmembrane domain This soluble form can activate pro-MMP2 [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
