MMP-2 and MMP-9 and Their Tissue Inhibitors in the Plasma of Preterm and Term Neonates

Abstract

Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are involved in a variety of physiologic growth and development and pathophysiologic inflammatory conditions. We hypothesized that 1) MMP-2 and -9 plasma activities and TIMP-1 and -2 plasma concentrations in preterm and term neonates were dependent on the gestational and postnatal age; and 2) the respective MMP and their inhibitors were deranged in the development of bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH) in preterm neonates. From 1998 to 1999, blood samples were collected from preterm neonates (25-36 wk gestation) with or without BPD and/or IVH as well as from healthy term (37-40 wk gestation) neonates during the first 28 d of life. MMP-2 and MMP-9 plasma activities were measured by zymography; TIMP-1 and TIMP-2 plasma concentrations were determined by ELISA. In neonates without BPD or IVH (n ϭ 50), MMP-2 and MMP-9 plasma activities both appeared to be gestational age dependent, with the highest levels observed in neonates of 33-36 wk gestation. TIMP-1 plasma concentration was highest in term neonates but no gestational difference was found in TIMP-2. Only MMP-9 showed a 50% decrease after d 1 in the first postnatal month. Twelve preterm infants with BPD and/or IVH had significantly lower MMP-2 but higher MMP-9 activity and higher TIMP-1 concentration than those of corresponding neonates without BPD or IVH. These findings show the gestational age-dependent expression of plasma MMP activities and their inhibitors. MMP and TIMP may be involved in the feto-neonatal development and may contribute to the pathogenesis of BPD and/or IVH in critically ill preterm neonates. MMP are a group of zinc-dependent endopeptidases involved in the process of tissue remodeling through the degradation of the ECM. Tissue remodeling occurs in various physiologic conditions, such as embryogenesis and wound healing, as well as in pathologic conditions, including inflammatory diseases, tumor cell invasion, and angiogenesis (1). Among the MMP, MMP-2 (gelatinase A: pro-enzyme, 72 kD, constitutive) and MMP-9 (gelatinase B: pro-enzyme, 92 kD, inducible) are of particular interest because of their novel roles other than tissue remodeling. Recently, MMP-2 has been found to play a role in acute disease processes such as platelet aggregation (2), the regulation of vascular tone (3), and myocardial dysfunction after ischemia-reperfusion (4). Whereas both MMP-2 and MMP-9 are activated through proteolytic cleavage and/or oxidative stress (5), the proteolytic function of MMP is at least in part inhibited by tissue inhibitors of MMP (TIMP) (6). Thus, imbalances between MMP and TIMP may result in an increased proteolytic activity and therefore promote the progression of pathologic conditions such as inflammatory and myocardial diseases (1, 4) and intracerebral hemorrhage (7).Both term and preterm neonates have to undergo various adaptive processes to environmental conditions ex utero, including an enhanced oxidative stress. However, the organ systems of...

Inhibition of MMP-9 Activity following Hypoxic Ischemia in the Developing Brain Using a Highly Specific Inhibitor

“…Importantly, MMP-9 activity has recently been implicated in the aetiology of injuries to the immature brain. Schulz et al [7] have demonstrated that plasma levels of MMP-9 were significantly higher in infants with intraventricular haemorrhage suggesting a possible role of peripheral MMP-9 in neonatal brain injury.…”

Infantile Chronic Recurrent Parotitis (ICRP): Analysis of Changes in the Expression of Parotid Salivary Proteins Associated with the Disease

“…They have also been observed in inflammatory pathologies of the child, as in chronic suppurative otitis media and in chronic lung diseases (Ekekezie et al, 2004;Jang et al, 2006). Both gelatinases have ben found in a variety of body fluids, namely, caphaloraquid fluid, tracheal secretion, middle ear secretion, gingival fluid, blood plasma and saliva (Ekekezie et al, 2004;Jang et al, 2006;Kettlun et al, 2003;Schulz et al, 2004;Valenzuela, 2000;Wu et al, 1997). Patients subjected to therapeutical irradiation of the maxillofacial territory have active and inactive forms of MMP-2 and MMP-9 in saliva and irradiation would increase the MMP-9 activity (Vuotila et al, 2002).…”

Detection of matalloproteinase-2-8-9 and tissue protease inhibitor serum levels in preterm babies with respiratory distress syndrome

“…MMP ve TIMP düzeylerinin preterm bebeklerde intraventriküler hemoraji ve bronkopulmoner displazi gelişimi ile ilişkili olduğunu ve MMP-2 ve MMP-9 düzeylerinin gestasyonel yaştan etkilendiğini bildirmiş-lerdir. 4 Ekekezie ve ark. kronik akciğer hastalığı olma riski olan hastalarda ilk hafta içerisinde TIMP-1 seviyesinin düşük, MMP-9/TIMP-1 oranının, TIMP-2 ve MMP-2 seviyelerinin düşük olduğunu bildirmişlerdir.…”

“…Entübasyon yada surfaktan ihtiyacı göstermeyen hafif ya da orta düzey RDS'li hastalar ayrıca incelenmemiştir. koryoamnionit ve intraventriküler kanama gibi patolojilerde MMP ve TIMP düzeylerinin değişiklik göstermesi, olayın sadece akciğer ile sınırlı olmadığını ve sistemik etkilerinin de olabileceğini göstermektedir 3,4 . Tüm bu nedenlerle serumda MMP ve TIMP düzeyinin belirlenmesinin akciğer hasarının göstergesi olabileceği düşünülmüştür.…”