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The Role of Monocyte-Derived Cells and Inflammation in Baboon Ductus

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The Role of Monocyte-Derived Cells and Inflammation in Baboon Ductus 0031-3998/05/5702-0254 PEDIATRIC RESEARCH Vol. 57, No. 2, 2005 Copyright © 2005 International Pediatric Research Foundation, Inc. Printed in U.S.A. The Role of Monocyte-Derived Cells and Inflammation in Baboon Ductus Arteriosus Remodeling NAHID WALEH, STEVEN SEIDNER, DONALD MCCURNIN, BRADLEY YODER, BAO MEI LIU, CHRISTINE ROMAN, FRANÇOISE MAURAY, AND RONALD I. CLYMAN Cardiovascular Research Institute [B.M.L., C.R., F.M., R.I.C.], Department of Pediatrics [R.I.C.], University of California, San Francisco, San Francisco, California 94143, Pharmaceutical Discovery Division [N.W.], SRI International, Menlo Park, California 94025, Department of Pediatrics [S.S., D.M.], Department of Pathology [B.Y.], University of Texas, San Antonio, Texas 78284 ABSTRACT Inflammatory processes play a crucial role in the pathogenesis remodeling (both endothelial cell layering and subendothelial of atherosclerosis and other vascular disorders. We hypothesized space thickening) was associated with the degree of mononuclear that ischemia of the ductus arteriosus might initiate an active cell adhesion. Similarly, the extent of vasa vasorum ingrowth inflammatory response that could play a role in ductus remodel- correlated with the invasion of CD68ϩ cells, from the adventitia ing and permanent closure. To test this hypothesis, we studied into the muscle media. Based on these data, we conclude that the effects of postnatal ductus construction on inflammatory pro- inflammatory response following postnatal ductus constriction cesses and remodeling in late-gestation fetal and newborn ba- may be as necessary for ductus remodeling as it is for athero- boons, and preterm newborn baboons. After postnatal ductus sclerotic remodeling. (Pediatr Res 57: 254–262, 2005) constriction, the expression of several genes known to be essen- tial for atherosclerotic remodeling [vascular cell adhesion mol- ecule (VCAM)-1, E-selectin, IL-8, macrophage colony stimulat- Abbreviations ing factor-1, CD154, interferon-␥, IL-6, and tumor necrosis IBU, ibuprofen factor-␣] was increased in the ductus wall. We were unable to ICAM, intercellular adhesion molecule detect intercellular adhesion molecule (ICAM)-1, ICAM-2, P- IFN-␥, interferon-␥ selectin, monocyte chemoattractant protein-1, or IL-1 by either INDO, indomethacin real-time PCR or immunohistochemistry. VCAM-1, which is L-NA, N-nitro-L-arginine newly expressed by luminal cells of the closed ductus, is an MCP, monocyte chemoattractant protein important ligand for the mononuclear cell adhesion receptor MMA, N-monomethyl-L-arginine-monoacetate VLA4. After postnatal constriction, VLA4ϩ monocytes/ MDH, malate dehydrogenase macrophages (CD68ϩ and CD14ϩ) and, to a lesser extent, TNF-␣, tumor necrosis factor-␣ T-lymphocytes adhered to the ductus wall. Neutrophils and VCAM, vascular cell adhesion molecule platelets were not observed. The extent of postnatal neointimal VEGF, vascular endothelial growth factor Closure of the full-term ductus arteriosus occurs in two hypoxia in the ductus’ muscle media that induces the following phases. First, smooth muscle constriction obstructs the ductus’ anatomic changes: luminal endothelial proliferation, subendo- lumen. Then, anatomic remodeling permanently occludes the thelial thickening, ingrowth of vasa vasorum, and cell death lumen. The initial constriction appears to be the required (1). The preterm newborn is capable of remodeling its ductus, stimulus for anatomic closure. During constriction, loss of just like the full-term newborn, if it can impede its luminal flow luminal and vasa vasorum flow produce a zone of ischemic- and develop the same degree of ischemic-hypoxia as found at term (2). Received March 9, 2004; accepted July 19, 2004. Although the cell death and ingrowth of vasa vasorum in the Correspondence: Ronald I. Clyman, M.D., Box 0544, HSE 1492, University of ductus wall appear to be due to ATP depletion (3,4) and VEGF California, San Francisco, 513 Parnassus Ave., San Francisco, CA 94143–0544, e-mail: induction (5), respectively, the mechanism(s) responsible for [email protected] Supported, in part, by U.S. Public Health Service National Heart, Lung, Blood Institute the neointimal changes are still unknown. It is now clear that grants HL 46691, HL 56061, and HL52636. inflammatory processes play a crucial role in the pathogenesis DOI: 10.1203/01.PDR.0000148278.64777.EF of several vascular disorders (6–9). The most studied model of 254 INFLAMMATION IN THE DUCTUS ARTERIOSUS 255 vascular inflammation is atherosclerosis, where the accumula- Therefore, MDH could be used as an internal control to normalize the degree of tion of monocytes/macrophages in the vessel wall plays an expression of any gene under investigation. We used the method of relative gene ⌬ Ϫ early role in remodeling (10). The monocytes/macrophages expression, where CT (MDH gene) represents the difference in cycle threshold between MDH and the individual gene of interest. Each unit of ⌬CT (MDH Ϫ elaborate numerous factors that help to orchestrate the subse- gene) represents a 2-fold increase in a gene’s mRNA. The more negative the ⌬CT quent neointimal changes (8,9). Recently, several cytokines— (MDH Ϫ gene), the fewer the number of starting copies of a gene. proinflammatory [IL-6 (11,12), TNF-␣ (13,14), IL-1 (13,14)], We have previously shown that the expression of VEGF mRNA in the ductus chemotactic [MCP-1 (15), IL-8 (16)], immunomodulatory [M- arteriosus correlates with the degree of smooth muscle hypoxia (5). In our CSF (10,17), IFN-␥ (18), CD154 (19,20)]—and adhesion mol- real-time PCR experiments, we used VEGF as a surrogate marker for hypoxia. ecules—P-selectin (21,22), E-selectin (21), ICAM-1 (22,23), Immunohistochemistry: in vivo preparation. Our primary goal was to examine the differences between preterm newborn ductus that remain patent VCAM-1 (23), and VLA4 integrin (24)—have been shown to after birth and those that close after birth. Preterm newborn baboons frequently play an essential role during atherosclerotic remodeling. fail to constrict their ductus and obstruct their luminal blood flow after birth We hypothesized that, after postnatal constriction and loss of unless they are treated with inhibitors of both prostaglandin and nitric oxide luminal blood flow, an active inflammatory process might play production (2). Therefore, we treated preterm newborn baboons with one of an important role in ductus arteriosus remodeling and perma- five protocols to obtain a sufficient number of closed ductus for immunohis- ϭ nent closure. In the studies described below, we found that, tochemical analysis: group 1—INDO alone (INDO, n 6); group 2—INDO plus L-NA (a nitric oxide synthase inhibitor) (INDOϩL-NA, n ϭ 6); group after postnatal constriction, monocytes/macrophages adhere to 3—INDO plus MMA (a nitric oxide synthase inhibitor) (INDOϩMMA, n ϭ the ductus wall, their accumulation appears to be related to the 6); group 4—ibuprofen alone (IBU, n ϭ 6); group 5—no treatment (control, types of cytokines and adhesion molecules induced after con- n ϭ 10). These treatment protocols have been previously described (2). INDO striction, and the extent of neointimal remodeling is directly (Indocin, 0.1 mg/kg/dose) was given intravenously at 24, 48, 72, 84, 96, 108, related to the degree of mononuclear cell adhesion. 120, and 132 h after delivery to animals in groups 1, 2, and 3. Groups 2 and 3 received continuous infusions of either L-NA (6 mg/kg/h) or MMA (20 mg/kg/h), respectively, starting at 50 h after delivery, which continued until METHODS necropsy. Group 4 received i.v. ibuprofen (Farmacon, Westport, CT) 10 mg/kg at 24 h and 5 mg/kg at 48, 72, 96, and 120 h after delivery. On the day of necropsy, the ductus was closed on Doppler exam in 3/6 All studies were approved by the committees on animal research at the INDO-treated, 6/6 INDOϩL-NA-treated, 6/6 INDOϩMMA-treated, 6/6 IBU- University of California San Francisco, the University of Texas Health Science treated, and 3/10 control preterm newborn baboons. We have previously Center, and the Southwest Foundation for Biomedical Research. shown that the histologic changes that occur during ductus remodeling depend We used fetal and newborn baboons (Papio sp., full term ϭ 185 d gestation) on the degree of ductus constriction and vessel wall ischemia, and not on the to examine the effects of ductus constriction on ductus remodeling. Animal pharmacologic manipulations used to produce the constriction (1,2). Therefore, care, surgery, and necropsy were performed as previously described (1,2). we sorted the ductus from the five different preterm newborn treatment groups Preterm [125 d gestation (68% of full term)] and mature (175 d gestation) fetal into two groups: immature newborn ductus closed at necropsy (n ϭ 24) and baboons were delivered by cesarean section and euthanized before breathing. immature newborn ductus open at necropsy (n ϭ 10). Preterm newborn baboons were delivered by cesarean section at 125 d Immunohistochemistry. Immunohistochemistry protocols were similar to gestation and were euthanized on d 6 after delivery. Mature full-term newborn those reported previously (2,26). Endothelial cells were detected with anti- baboons were euthanized between 1 and 2 d after spontaneous full-term endothelial nitric oxide synthase (Clone 3, BD Biosciences, San Jose, CA) and delivery. anti-CD31 (9G11,R&DSystems, Minneapolis, MN). Both antibodies Our primary goal was to examine the difference in inflammatory response showed identical findings. Antibodies against the following leukocyte antigens between
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