Low levels of tissue inhibitor of metalloproteinase-2 at birth may be associated with subsequent development of bronchopulmonary dysplasia in preterm infants

Abstract

PurposeBronchopulmonary dysplasia (BPD) is characterized by inflammation with proteolytic damage to the lung extracellular matrix. The results from previous studies are inconsistent regarding the role of proteinases and antiproteinases in the development of BPD. The aim of the present study was to investigate whether matrix metalloproteinase (MMP)-8, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2, and TIMP-1 levels in the serum of preterm infants at birth are related to the development of BPD.MethodsSerum was collected from 62 preterm infants at birth and analyzed for MMP-8, MMP-9, TIMP-2, and TIMP-1 by using enzyme-linked immunosorbent assay. MMPs and TIMPs were compared in BPD (n=24) and no BPD groups (n=38). Clinical predictors of BPD (sex, birth weight, gestational age, etc.) were assessed for both groups. The association between predictors and outcome, BPD, was assessed by using multivariate logistic regression.ResultsSex, birth weight, and mean gestational age were similar between the groups. BPD preterm infants had significantly lower TIMP-2 levels at birth compared with no BPD preterm infants (138.1±23.0 ng/mL vs. 171.8±44.1 ng/mL, P=0.027). No significant difference was observed in MMP-8, MMP-9, and TIMP-1 levels between the two groups. Multivariate logistic regression analysis indicated that the TIMP-2 levels were predictive of BPD after adjusting for sex, birth weight, gestational age, proteinuric preeclampsia, and intraventricular hemorrhage (β=-0.063, P=0.041).ConclusionLow TIMP-2 serum levels at birth may be associated with the subsequent development of BPD in preterm infants.

Injured Achilles Tendons Treated with Adipose-Derived Stem Cells Transplantation and GDF-5

“…Regarding the expression of genes related to tissue remodeling, Mmp2 , Mmp8 , Mmp9 , and Timp2 , higher expression of Mmp2 and Timp2 was observed in the ASC group in relation only to the ASC+GDF5 group. The literature describes the increased expression and activity of these MMPs during tendon repair processes [ 8 ], since previous studies of our group showed a direct relationship between the greater activity of MMP-2 and greater organization of the ECM of tendons [ 36 , 65 , 66 ], corroborating with the results from the present study. It is important to emphasize that the larger organization of the collagen fibers in the T1 region was also observed in the group treated with ADMSC only.…”

Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia

“…In addition, protease activity regulates the abundance of other proteinaceous mediators of lung development, such as receptors, and proteases both generate matrikines and other signaling molecules and regulate (through degradation) the abundance of these signaling molecules, which orchestrate lung development (265,354). To date, both neutrophil elastase and matrix metalloproteinase (MMP) members have receivedand continue to receive-attention, with one recent report suggesting that low serum levels of tissue inhibitor of metalloproteinases inhibitor-2 (TIMP-2) at birth may be associated with subsequent development of BPD (278). Along similar lines, another recent study generated an Adamts18 [encoding a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 18]-knockout mouse (38), where decreased cellularity of septa was evident by visual inspection of lung sections, suggesting that ADAMTS18 plays a causal role in alveolarization.…”

“…Given the pathogenic roles ascribed to MMPs and MMP inhibitors, it is noteworthy that low TIMP-2 serum levels at birth have recently been described to be associated with the subsequent development of BPD in preterm infants (278). Furthermore, secreted protein, acidic, rich in cysteine (SPARC; also called osteonectin) was also recently been documented to predict the development of BPD (425).…”

Differential Expression of Angiogenic Gene Networks during Post-natal Lung Alveolarization

“…Indeed, aberrant regulation of MMPs and TIMPs is strongly correlated to decreased collagen turnover in BPD fibrosis [19]. Low levels of MMP2 and higher MMP3, MMP9, and TIMP2 at birth were predictive biomarkers indicating increased risk of BPD [20][21][22]. Exposure of neonatal mice to chronic hypoxia resulted in upregulation of MMP2 and downregulation of TIMP2, while hyperoxia decreased MMP9 and TIMP1 activity [18].…”