Two N-terminal ends of human type XVIII collagen chains have recently been identified. The two chains have different signal peptides and variant N-terminal noncollagenous NC1 domains of 493 (NC1-493) and 303 (NC1-303) amino acid residues , respectively, but share 301 residues of their NC1 domains as well as the collagenous and C-terminal noncollagenous portions of the molecule. Antibodies were produced against the NC1 region common to both human ␣1(XVIII) chain variants and against NC1 sequences specific to the long variant and were used in combination with in situ hybridization to localize this collagen in a number of human tissues. They were also used for Western blotting , which resulted in detection of overlapping high-molecular weight bands above the 200-kd standard in a kidney extract. Heparin lyase II and heparin lyase III digestions of kidney and placenta extracts indicated that at least in these tissues, type XVIII collagen contains heparin sulfate glycosaminoglycan side chains. Type XVIII collagen was found to be a ubiquitous basement membrane component , occurring prominently at vascular and epithelial basement membranes throughout the body. Comparison of the expression of the NC1-493 and NC1-303 variants revealed marked differences. The short variant was found in most conventional basement membranes , including blood vessels and the various epithelial structures , and around muscular structures. The long variant was expressed very strongly in liver , where it was virtually the only variant in the liver sinusoids , and it occurred only in minor amounts elsewhere. Thus , the 192 N-terminal residues specific to the long variant apparently confer some functional property needed above all in the liver sinusoids , but also at certain other locations. (Am J Pathol 1998, 153:611-626) Type XVIII collagen is an extracellular matrix protein recently identified by cDNA cloning.1-4 Elucidation of the complete mouse chain revealed it to be homologous with the previously identified type XV collagen, 5-7 and it has been suggested that type XV and XVIII collagens together form a subgroup of MULTIPLEXINs (multiple triple-helix domains with interruptions) within the collagen family.2 The mouse type XVIII collagen differs strikingly from type XV by the presence of variant polypeptide forms characterized by three N-terminal noncollagenous domains of differing lengths. 8,9 Interestingly, the longest ␣1(XVIII) chain form has a motif of 10 cysteine residues homologous to the extracellular part of the frizzled receptors involved in the Wingless signaling pathway in Drosophila. 10We have recently reported also the full-length human type XVIII collagen cDNAs that encode 1516-or 1336-amino acid residue ␣1(XVIII) chains. 11 The two chains have different signal peptides and variant N-terminal noncollagenous NC1 domains of 493 (NC1-493) and 303 (NC1-303) amino acid residues, respectively, but share the last 301 residues of their NC1 domains, a 688-residue collagenous sequence (COL1 to COL10) with nine interruptions (NC2 to NC10), ...

Major cause of prematurity is spontaneous preterm birth (PTB) associated with intrauterine inflammation. Our aim was to establish a model of endotoxin Lipopolysaccharide-induced PTB of live-born pups and to study early immune activation in fetal and maternal compartments. Expression of several proteins that bind microbes (Toll-like receptors TLR4, TLR2; surfactant proteins SP-A, SP-D) was analyzed. At 16 or 17 d of gestation, C57BL/6 dams received a single dose of intraperitoneal LPS, leading to PTB within 17 h. Cytokine levels increased in maternal serum, followed by a modest increase in fetal serum and in amniotic fluid. In uterus, placenta, and fetal membranes, LPS mostly increased the expressions of TLR, SPs, and cytokines. The number of TLR2-positive macrophages increased in labyrinthine placenta. In fetal lung, intestine, liver, and brain there were modest changes in cytokine expressions. In fetal lung, SP and TLR mRNAs decreased and TLR2-positive macrophages redistributed around vessels. LPS-induced fetal deaths associated with early age (16 d gestation) rather than with proinflammatory activation. Here we propose that maternal LPS response leads to PTB and acute decrease of immune proteins in epithelial lining of fetal lung. Instead, acceleration of lung maturity has been previously observed in intraamniotic inflammation. (Pediatr Res 63: 280-286, 2008) P rematurity is the main cause of perinatal morbidity and mortality in developed countries. Altogether, 50 -70% of preterm births (PTBs) in humans are due to spontaneous onset of premature labor (1). There is a strong relationship between systemic or intrauterine infection and preterm delivery. Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, causes PTB in animals and has been implicated as a factor triggering preterm labor in humans (2). Different model systems have been established to study the induced PTB in mammalian species (3,4). The inflammatory models applied to mice involve intraperitoneal, intrauterine, or intraamniotic administration of heat-killed bacteria or bacterial products (5-7). Depending on the dose, gestational age, and site of exposure, the consequences of LPS-induced inflammatory response are variable. However, the administration of LPS has mostly resulted in fetal death or the delivery of dead fetuses (6 -11).The proposed sequence of inflammatory mediators leading to preterm labor and delivery involves the production of proinflammatory cytokines in uterus, placental tissue, and fetal tissues as a response to bacterial toxins. The cytokines, in turn, initiate the synthesis of secondary mediators, e.g., prostaglandins and matrix metalloproteinases involved in the preterm delivery (2,4). It has been proposed that fetal death results from a maternal response rather than fetal sensitivity to LPS (12,13).The innate immune system involved in nonclonal host defense is likely to influence fetal outcome. Toll-like receptors (TLRs) and collectins serve as signaling receptors for pathogen-associated molecular patterns...

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in several diseases. This study was undertaken to investigate the mRNA synthesis of MMP2, MMP9, membrane-type 1 (MT1)-MMP, and matrix metalloproteinase inhibitors TIMP1 and TIMP2 by in situ hybridization in a set of heart mitral and aortic valves operatively removed due to degenerative or inflammatory valvular diseases. The material consisted of 21 valves, eight with endocarditis and 13 with a degenerative valvular disease. The samples were studied by in situ hybridization with specific probes for MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2. Synthesis of MMP2 mRNA was found in seven valves, five with endocarditis and two with degenerative valvular disease. Signals for MMP9 mRNA were found in two cases with endocarditis and five cases with degenerative valvular disease. No signal for MT1-MMP mRNA was found in the lesions. TIMP1 mRNA, on the other hand, was found in 17 cases, both endocarditis and degenerative valvular disease. TIMP2 mRNA was found in three cases of endocarditis. The signals for MMP2, MMP9, TIMP1, and TIMP2 mRNA were localized in endothelial cells and in fibroblast-like cells expressing alpha-smooth muscle actin, thus showing myofibroblast-type differentiation. The results show that matrix metalloproteinases MMP2 and MMP9, and matrix metalloproteinase inhibitors TIMP1 and TIMP2 mRNAs are synthesized in diseased valves and suggest that they may contribute to matrix remodelling in valvular disease.

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