{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T16:42:18Z","timestamp":1769186538259,"version":"3.49.0"},"reference-count":47,"publisher":"The Endocrine Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,9,1]]},"abstract":"<jats:p>The pathogenesis of pulmonary hypertension (PH) includes an inflammatory response. Thymulin, a zinc-dependent thymic hormone, has important immunobiological effects by inhibiting various proinflammatory cytokines and chemokines. We investigated morphological and hemodynamic effects of thymulin administration in a rat model of monocrotaline (MCT)-induced PH, as well as the pattern of proinflammatory cytokine gene expression and the intracellular pathways involved. Adult Wistar rats received an injection of MCT (60 mg\/kg, sc) or an equal volume of saline. One day after, the animals randomly received during 3 wk an injection of saline, vehicle (zinc plus carboxymethyl cellulose), or thymulin (100 ng\/kg, sc, daily). At d 23\u201325, the animals were anesthetized for hemodynamic recordings, whereas heart and lungs were collected for morphometric and molecular analysis. Thymulin prevented morphological, hemodynamic, and inflammatory cardiopulmonary profile characteristic of MCT-induced PH, whereas part of these effects were also observed in MCT-treated animals injected with the thymulin\u2019s vehicle containing zinc. The pulmonary thymulin effect was likely mediated through suppression of p38 pathway.<\/jats:p>","DOI":"10.1210\/en.2008-0018","type":"journal-article","created":{"date-parts":[[2008,5,30]],"date-time":"2008-05-30T00:46:21Z","timestamp":1212108381000},"page":"4367-4373","source":"Crossref","is-referenced-by-count":35,"title":["Thymulin Inhibits Monocrotaline-Induced Pulmonary Hypertension Modulating Interleukin-6 Expression and Suppressing p38 Pathway"],"prefix":"10.1210","volume":"149","author":[{"given":"Tiago","family":"Henriques-Coelho","sequence":"first","affiliation":[{"name":"Department of Physiology (T.H.-C., S.M.O., R.R.-A., A.L.N., M.S., F.L.F.C., A.B.-N., A.F.L.-M.), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Si\u0301lvia Marta","family":"Oliveira","sequence":"first","affiliation":[{"name":"Department of Physiology (T.H.-C., S.M.O., R.R.-A., A.L.N., M.S., F.L.F.C., A.B.-N., A.F.L.-M.), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Rute S.","family":"Moura","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS) (R.S.M., C.N.-S., J.C.-P.), School of Health Sciences, University of Minho, 4704-553 Braga, Portugal"}]},{"suffix":"Jr.","given":"Roberto","family":"Roncon-Albuquerque","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS) (R.S.M., C.N.-S., J.C.-P.), School of Health Sciences, University of Minho, 4704-553 Braga, Portugal"}]},{"given":"Ana Lui\u0301sa","family":"Neves","sequence":"first","affiliation":[{"name":"Department of Physiology (T.H.-C., S.M.O., R.R.-A., A.L.N., M.S., F.L.F.C., A.B.-N., A.F.L.-M.), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Ma\u0301rio","family":"Santos","sequence":"first","affiliation":[{"name":"Department of Physiology (T.H.-C., S.M.O., R.R.-A., A.L.N., M.S., F.L.F.C., A.B.-N., A.F.L.-M.), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Cristina","family":"Nogueira-Silva","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS) (R.S.M., C.N.-S., J.C.-P.), School of Health Sciences, University of Minho, 4704-553 Braga, Portugal"}]},{"given":"Filipe","family":"La Fuente Carvalho","sequence":"first","affiliation":[{"name":"Department of Physiology (T.H.-C., S.M.O., R.R.-A., A.L.N., M.S., F.L.F.C., A.B.-N., A.F.L.-M.), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Ana","family":"Branda\u0303o-Nogueira","sequence":"first","affiliation":[{"name":"Department of Physiology (T.H.-C., S.M.O., R.R.-A., A.L.N., M.S., F.L.F.C., A.B.-N., A.F.L.-M.), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Jorge","family":"Correia-Pinto","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS) (R.S.M., C.N.-S., J.C.-P.), School of Health Sciences, University of Minho, 4704-553 Braga, Portugal"}]},{"given":"Adelino F.","family":"Leite-Moreira","sequence":"first","affiliation":[{"name":"Department of Physiology (T.H.-C., S.M.O., R.R.-A., A.L.N., M.S., F.L.F.C., A.B.-N., A.F.L.-M.), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]}],"member":"80","published-online":{"date-parts":[[2008,5,29]]},"reference":[{"issue":"Suppl S","key":"2020071612334281100_R1","doi-asserted-by":"crossref","first-page":"5S","DOI":"10.1016\/j.jacc.2004.02.037","article-title":"Clinical classification of pulmonary hypertension","volume":"43","author":"Simonneau","year":"2004","journal-title":"J Am Coll Cardiol"},{"key":"2020071612334281100_R2","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1016\/j.ehj.2004.09.014","article-title":"Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology.","volume":"25","author":"Galie","year":"2004","journal-title":"Eur Heart J"},{"key":"2020071612334281100_R3","first-page":"275","article-title":"Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension.","volume":"144","author":"Tuder","year":"1994","journal-title":"Am J Pathol"},{"key":"2020071612334281100_R4","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0046-8177(97)90032-0","article-title":"Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection.","volume":"28","author":"Cool","year":"1997","journal-title":"Hum Pathol"},{"key":"2020071612334281100_R5","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1164\/ajrccm.151.5.7735624","article-title":"Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension.","volume":"151","author":"Humbert","year":"1995","journal-title":"Am J Respir Crit Care Med"},{"key":"2020071612334281100_R6","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1164\/rccm.2106007","article-title":"CX(3)C chemokine fractalkine in pulmonary arterial hypertension.","volume":"165","author":"Balabanian","year":"2002","journal-title":"Am J Respir Crit Care Med"},{"key":"2020071612334281100_R7","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1164\/ajrccm.165.4.2012112","article-title":"Chemokine RANTES in severe pulmonary arterial hypertension.","volume":"165","author":"Dorfmuller","year":"2002","journal-title":"Am J Respir Crit Care Med"},{"key":"2020071612334281100_R8","author":"Fartoukh","year":"1998"},{"key":"2020071612334281100_R9","first-page":"126","article-title":"Monocrotaline induces interleukin-6 mRNA expression in rat lungs.","volume":"1","author":"Bhargava","year":"1999","journal-title":"Heart Dis"},{"key":"2020071612334281100_R10","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1136\/ard.55.8.561","article-title":"Improvement of severe pulmonary hypertension in a patient with SLE.","volume":"55","author":"Karmochkine","year":"1996","journal-title":"Ann Rheum Dis"},{"key":"2020071612334281100_R11","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1164\/ajrccm.163.2.2006093","article-title":"40-O- (2-hydroxyethyl)-rapamycin attenuates pulmonary arterial hypertension and neointimal formation in rats.","volume":"163","author":"Nishimura","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"2020071612334281100_R12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1465-9921-8-15","article-title":"Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice.","volume":"8","author":"Paddenberg","year":"2007","journal-title":"Respir Res"},{"key":"2020071612334281100_R13","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.bbrc.2006.08.109","article-title":"Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats.","volume":"349","author":"Suzuki","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612334281100_R14","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1183\/09031936.03.00038903","article-title":"Inflammation in pulmonary arterial hypertension.","volume":"22","author":"Dorfmuller","year":"2003","journal-title":"Eur Respir J"},{"key":"2020071612334281100_R15","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/S0761-8425(07)91571-5","article-title":"[Animal models of pulmonary arterial hypertension.]","volume":"24(4 Pt 1)","author":"Naeije","year":"2007","journal-title":"Rev Mal Respir"},{"key":"2020071612334281100_R16","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1165\/ajrcmb.11.6.7946395","article-title":"Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline.","volume":"11","author":"Voelkel","year":"1994","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2020071612334281100_R17","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1159\/000237166","article-title":"Pulmonary hypertension in rats. 2. Role of interleukin-6.","volume":"108","author":"Miyata","year":"1995","journal-title":"Int Arch Allergy Immunol"},{"key":"2020071612334281100_R18","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1378\/chest.119.2.554","article-title":"Effect of a serotonin receptor antagonist on interleukin-6-induced pulmonary hypertension in rats.","volume":"119","author":"Miyata","year":"2001","journal-title":"Chest"},{"key":"2020071612334281100_R19","doi-asserted-by":"crossref","first-page":"8252","DOI":"10.1128\/JVI.76.16.8252-8264.2002","article-title":"Transcriptional regulation of the interleukin-6 gene of human herpesvirus 8 (Kaposi\u2019s sarcoma-associated herpesvirus).","volume":"76","author":"Deng","year":"2002","journal-title":"J Virol"},{"key":"2020071612334281100_R20","first-page":"1605","article-title":"[Biochemical characterization of a circulating thymic factor.]","volume":"283","author":"Bach","year":"1976","journal-title":"C R Acad Sci Hebd Seances Acad Sci D"},{"key":"2020071612334281100_R21","doi-asserted-by":"crossref","first-page":"8040","DOI":"10.1016\/S0021-9258(17)40932-X","article-title":"Structural study of circulating thymic factor: a peptide isolated from pig serum. I. Isolation and purification.","volume":"252","author":"Dardenne","year":"1977","journal-title":"J Biol Chem"},{"key":"2020071612334281100_R22","doi-asserted-by":"crossref","first-page":"8045","DOI":"10.1016\/S0021-9258(17)40933-1","article-title":"Structural study of circulating thymic factor: a peptide isolated from pig serum. II. Amino acid sequence.","volume":"252","author":"Pleau","year":"1977","journal-title":"J Biol Chem"},{"key":"2020071612334281100_R23","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/j.1749-6632.1975.tb29068.x","article-title":"Isolation, biochemical characteristics, and biological activity of a circulating thymic hormone in the mouse and in the human.","volume":"249","author":"Bach","year":"1975","journal-title":"Ann NY Acad Sci"},{"key":"2020071612334281100_R24","doi-asserted-by":"crossref","first-page":"5370","DOI":"10.1073\/pnas.79.17.5370","article-title":"Contribution of zinc and other metals to the biological activity of the serum thymic factor.","volume":"79","author":"Dardenne","year":"1982","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612334281100_R25","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1177\/32.9.6379040","article-title":"Thymic hormone-containing cells. V. Immunohistological detection of metallothionein within the cells bearing thymulin (a zinc-containing hormone) in human and mouse thymuses.","volume":"32","author":"Savino","year":"1984","journal-title":"J Histochem Cytochem"},{"key":"2020071612334281100_R26","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1210\/endo-125-1-3","article-title":"Neuroendocrine control of thymic hormonal production. I. Prolactin stimulates in vivo and in vitro the production of thymulin by human and murine thymic epithelial cells.","volume":"125","author":"Dardenne","year":"1989","journal-title":"Endocrinology"},{"key":"2020071612334281100_R27","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1006\/bbrc.2000.3155","article-title":"Immunomodulatory potential of thymulin-Zn(2+) in the alveolar epithelium: amelioration of endotoxin-induced cytokine release and partial amplification of a cytoprotective IL-10-sensitive pathway.","volume":"274","author":"Haddad","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612334281100_R28","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1046\/j.1365-2249.2001.01493.x","article-title":"FTS reduces bleomycin-induced cytokine and chemokine production and inhibits pulmonary fibrosis in mice.","volume":"124","author":"Yara","year":"2001","journal-title":"Clin Exp Immunol"},{"key":"2020071612334281100_R29","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/j.bcp.2005.08.002","article-title":"Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.","volume":"70","author":"Kohda","year":"2005","journal-title":"Biochem Pharmacol"},{"key":"2020071612334281100_R30","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1248\/bpb.28.2087","article-title":"Protective effect of serum thymic factor, FTS, on cephaloridine-induced nephrotoxicity in rats.","volume":"28","author":"Kohda","year":"2005","journal-title":"Biol Pharm Bull"},{"key":"2020071612334281100_R31","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.exger.2007.12.008","article-title":"In vitro and in vivo effects of zinc on cytokine signalling in human T cells.","volume":"43","author":"Varin","year":"2008","journal-title":"Exp Gerontol"},{"key":"2020071612334281100_R32","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.exger.2007.10.013","article-title":"Clinical, immunological, anti-inflammatory and antioxidant roles of zinc.","volume":"43","author":"Prasad","year":"2008","journal-title":"Exp Gerontol"},{"key":"2020071612334281100_R33","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S1567-5769(02)00236-9","article-title":"In vivo thymulin treatments enhance avian lung natural killer cell cytotoxicity in response to infectious bronchitis virus.","volume":"3","author":"Oliver","year":"2003","journal-title":"Int Immunopharmacol"},{"key":"2020071612334281100_R34","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0145-305X(01)00052-0","article-title":"The effects of thymulin on macrophage responsiveness to interferon-\u03b3.","volume":"26","author":"Orringer","year":"2002","journal-title":"Dev Comp Immunol"},{"key":"2020071612334281100_R35","doi-asserted-by":"crossref","first-page":"L370","DOI":"10.1152\/ajplung.00200.2001","article-title":"MEK-1\/2 inhibition reduces branching morphogenesis and causes mesenchymal cell apoptosis in fetal rat lungs","volume":"282","author":"Kling","year":"2002","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2020071612334281100_R36","doi-asserted-by":"crossref","first-page":"H2885","DOI":"10.1152\/ajpheart.01122.2003","article-title":"Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension","volume":"287","author":"Henriques-Coelho","year":"2004","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2020071612334281100_R37","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/978-1-4684-5877-0_64","article-title":"Lung vascular injury from monocrotaline pyrrole, a putative hepatic metabolite.","volume":"283","author":"Roth","year":"1991","journal-title":"Adv Exp Med Biol"},{"key":"2020071612334281100_R38","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.jtcvs.2004.03.003","article-title":"Specific inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates vascular proliferation in monocrotaline-induced pulmonary hypertension in rats.","volume":"128","author":"Lu","year":"2004","journal-title":"J Thorac Cardiovasc Surg"},{"key":"2020071612334281100_R39","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1161\/ATVBAHA.107.141200","article-title":"Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension.","volume":"27","author":"Morty","year":"2007","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2020071612334281100_R40","doi-asserted-by":"crossref","first-page":"L1028","DOI":"10.1152\/ajplung.00479.2005","article-title":"Zn2+-induced IL-8 expression involves AP-1, JNK, and ERK activities in human airway epithelial cells","volume":"290","author":"Kim","year":"2006","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2020071612334281100_R41","first-page":"L551","article-title":"Activation of MAPKs in human bronchial epithelial cells exposed to metals","volume":"275(3 Pt 1)","author":"Samet","year":"1998","journal-title":"Am J Physiol"},{"key":"2020071612334281100_R42","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.cellsig.2003.12.008","article-title":"Structure and regulation of MAPK phosphatases.","volume":"16","author":"Farooq","year":"2004","journal-title":"Cell Signal"},{"key":"2020071612334281100_R43","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0014-2999(94)90691-2","article-title":"Prevention of diabetes by thymic hormone in alloxan-treated rats.","volume":"257","author":"Yamanouchi","year":"1994","journal-title":"Eur J Pharmacol"},{"key":"2020071612334281100_R44","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/BF01718589","article-title":"In vivo administration of serum thymic factor (FTS) prevents EMC-D virus-induced diabetes and myocarditis in BALB\/cAJcl mice.","volume":"141","author":"Mizutani","year":"1996","journal-title":"Arch Virol"},{"issue":"Pt 1","key":"2020071612334281100_R45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj20030407","article-title":"Principles of interleukin (IL)-6-type cytokine signalling and its regulation","volume":"374","author":"Heinrich","year":"2003","journal-title":"Biochem J"},{"key":"2020071612334281100_R46","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1203\/01.pdr.0000242300.09427.3b","article-title":"IL-6 is constitutively expressed during lung morphogenesis and enhances fetal lung explant branching.","volume":"60","author":"Nogueira-Silva","year":"2006","journal-title":"Pediatr Res"},{"key":"2020071612334281100_R47","doi-asserted-by":"crossref","first-page":"L1473","DOI":"10.1152\/ajplung.00197.2006","article-title":"Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle","volume":"292","author":"Hagen","year":"2007","journal-title":"Am J Physiol Lung Cell Mol Physiol"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/9\/4367\/8999904\/endo4367.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/149\/9\/4367\/8999904\/endo4367.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,11]],"date-time":"2021-09-11T08:33:44Z","timestamp":1631349224000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/149\/9\/4367\/2455627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,5,29]]},"references-count":47,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2008,9,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2008-0018","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,5,29]]}}}