{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:47:39Z","timestamp":1792608459155,"version":"4.5.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2012,11,1]],"date-time":"2012-11-01T00:00:00Z","timestamp":1351728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling. Recent studies have revealed that immune and inflammatory responses play a crucial role in pathogenesis of idiopathic PAH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To systematically evaluate the number and cross-sectional distribution of inflammatory cells in different sizes of pulmonary arteries from explanted lungs of patients with idiopathic PAH versus healthy donor lungs and to demonstrate functional relevance by blocking stromal-derived factor-1 by the Spiegelmer NOX-A12 in monocrotaline-induced pulmonary hypertension in rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Immunohistochemistry was performed on lung tissue sections from patients with idiopathic PAH and healthy donors. All positively stained cells in whole-lung tissue sections, surrounding the vessels, and in the different compartments of the vessels were counted. To study the effects of blocking SDF-1, rats with monocrotaline-induced pulmonary hypertension were treated with NOX-A12 from Day 21 to Day 35 after monocrotaline administration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>We found a significant increase of the perivascular number of macrophages (CD68+), macrophages\/monocytes (CD14+), mast cells (toluidine blue+), dendritic cells (CD209+), T cells (CD3+), cytotoxic T cells (CD8+), and helper T cells (CD4+) in vessels of idiopathic PAH lungs compared with control subjects. FoxP3+ mononuclear cells were significantly decreased. In the monocrotaline model, the NOX-A12\u2013induced reduction of mast cells, CD68+ macrophages, and CD3+ T cells was associated with improvement of hemodynamics and pulmonary vascular remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings reveal altered perivascular inflammatory cell infiltration in pulmonary vascular lesions of patients with idiopathic pulmonary arterial hypertension. Targeting attraction of inflammatory cells by blocking stromal-derived factor-1 may be a novel approach for treatment of PAH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201202-0335oc","type":"journal-article","created":{"date-parts":[[2012,9,7]],"date-time":"2012-09-07T01:50:18Z","timestamp":1346982618000},"page":"897-908","source":"Crossref","is-referenced-by-count":386,"title":["Immune and Inflammatory Cell Involvement in the Pathology of Idiopathic Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"186","author":[{"given":"Rajkumar","family":"Savai","sequence":"first","affiliation":[{"name":"Department of Lung Development and Remodelling, Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soni S.","family":"Pullamsetti","sequence":"additional","affiliation":[{"name":"Department of Lung Development and Remodelling, Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany"},{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Kolbe","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Bieniek","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Voswinckel","sequence":"additional","affiliation":[{"name":"Department of Lung Development and Remodelling, Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany"},{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludger","family":"Fink","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Giessen and Marburg Lung Center, Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Scheed","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Vienna, Vienna, Austria; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Ritter","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhola K.","family":"Dahal","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Vater","sequence":"additional","affiliation":[{"name":"NOXXON Pharma AG, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Klussmann","sequence":"additional","affiliation":[{"name":"NOXXON Pharma AG, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein A.","family":"Ghofrani","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Weissmann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Klepetko","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Vienna, Vienna, Austria; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gamal A.","family":"Banat","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Seeger","sequence":"additional","affiliation":[{"name":"Department of Lung Development and Remodelling, Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany"},{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich","family":"Grimminger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph T.","family":"Schermuly","sequence":"additional","affiliation":[{"name":"Department of Lung Development and Remodelling, Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany"},{"name":"Department of Internal Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,11,1]]},"reference":[{"key":"2026032101051825300_bib1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/1817-1737.37832","article-title":"Pulmonary hypertension: past, present and future","volume":"3","author":"Barst","year":"2008","journal-title":"Ann Thorac Med"},{"key":"2026032101051825300_bib2","doi-asserted-by":"crossref","first-page":"S108","DOI":"10.1016\/j.jacc.2009.04.014","article-title":"Future perspectives for the treatment of pulmonary arterial hypertension","volume":"54","author":"Ghofrani","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2026032101051825300_bib3","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1016\/j.jacc.2009.04.012","article-title":"Updated clinical classification of pulmonary hypertension","volume":"54","author":"Simonneau","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2026032101051825300_bib4","doi-asserted-by":"crossref","first-page":"50S","DOI":"10.1378\/chest.114.1_Supplement.50S","article-title":"Chemokine macrophage inflammatory protein-1alpha MMA expression in lung biopsy specimens of primary pulmonary hypertension","volume":"114","author":"Fartoukh","year":"1998","journal-title":"Chest"},{"key":"2026032101051825300_bib5","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":"2026032101051825300_bib6","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.1161\/01.CIR.102.22.2720","article-title":"Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy","volume":"102","author":"Sakamaki","year":"2000","journal-title":"Circulation"},{"key":"2026032101051825300_bib7","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":"2026032101051825300_bib8","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":"2026032101051825300_bib9","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1164\/rccm.200610-1559OC","article-title":"Role of endothelium-derived cc chemokine ligand 2 in idiopathic pulmonary arterial hypertension","volume":"176","author":"Sanchez","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101051825300_bib10","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":"2026032101051825300_bib11","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1164\/rccm.201201-0164OC","article-title":"Modern age pathology of pulmonary arterial hypertension","volume":"186","author":"Stacher","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101051825300_bib12","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1183\/09031936.00094706","article-title":"Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension","volume":"29","author":"Perros","year":"2007","journal-title":"Eur Respir J"},{"key":"2026032101051825300_bib13","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1164\/rccm.201105-0927OC","article-title":"Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension","volume":"185","author":"Perros","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101051825300_bib14","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1159\/000111548","article-title":"Increased regulatory and decreased CD8+ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension","volume":"75","author":"Ulrich","year":"2008","journal-title":"Respiration"},{"key":"2026032101051825300_bib15","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ajpath.2011.03.004","article-title":"Dual blockade of the homeostatic chemokine CXCL12 and the proinflammatory chemokine CCL2 has additive protective effects on diabetic kidney disease","volume":"179","author":"Darisipudi","year":"2011","journal-title":"Am J Pathol"},{"key":"2026032101051825300_bib16","author":"Savai"},{"key":"2026032101051825300_bib17","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1136\/jcp.44.12.1003","article-title":"Lung mast cells in plexogenic pulmonary arteriopathy","volume":"44","author":"Heath","year":"1991","journal-title":"J Clin Pathol"},{"key":"2026032101051825300_bib18","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1165\/rcmb.2008-0153OC","article-title":"The noncanonical WNT pathway is operative in idiopathic pulmonary arterial hypertension","volume":"40","author":"Laumanns","year":"2009","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026032101051825300_bib19","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.jacc.2009.04.006","article-title":"Inflammation, growth factors, and pulmonary vascular remodeling","volume":"54","author":"Hassoun","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2026032101051825300_bib20","doi-asserted-by":"crossref","first-page":"L238","DOI":"10.1152\/ajplung.90591.2008","article-title":"Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment","volume":"297","author":"Burke","year":"2009","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026032101051825300_bib21","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1136\/thx.2008.106435","article-title":"Contribution of inflammation to the pathology of idiopathic pulmonary arterial hypertension in children","volume":"64","author":"Hall","year":"2009","journal-title":"Thorax"},{"key":"2026032101051825300_bib22","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1152\/japplphysiol.00840.2004","article-title":"Hypoxia, leukocytes, and the pulmonary circulation","volume":"98","author":"Stenmark","year":"2005","journal-title":"J Appl Physiol"},{"key":"2026032101051825300_bib23","doi-asserted-by":"crossref","first-page":"659","DOI":"10.2353\/ajpath.2006.050599","article-title":"Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte\/macrophage lineage","volume":"168","author":"Frid","year":"2006","journal-title":"Am J Pathol"},{"key":"2026032101051825300_bib24","doi-asserted-by":"crossref","first-page":"234","DOI":"10.2174\/157016109787455635","article-title":"Macrophages: promising targets for the treatment of atherosclerosis","volume":"7","author":"Wilson","year":"2009","journal-title":"Curr Vasc Pharmacol"},{"key":"2026032101051825300_bib25","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1161\/CIRCULATIONAHA.110.978627","article-title":"Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension","volume":"123","author":"Vergadi","year":"2011","journal-title":"Circulation"},{"key":"2026032101051825300_bib26","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1084\/jem.193.11.1327","article-title":"Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor","volume":"193","author":"Wu","year":"2001","journal-title":"J Exp Med"},{"key":"2026032101051825300_bib27","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.rmed.2009.10.004","article-title":"T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension","volume":"104","author":"Austin","year":"2010","journal-title":"Respir Med"},{"key":"2026032101051825300_bib28","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.jacc.2006.09.049","article-title":"Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease","volume":"49","author":"Levy","year":"2007","journal-title":"J Am Coll Cardiol"},{"key":"2026032101051825300_bib29","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0002-9440(10)65269-8","article-title":"T lymphocytes induce endothelial cell matrix metalloproteinase expression by a cd40l-dependent mechanism: implications for tubule formation","volume":"154","author":"Mach","year":"1999","journal-title":"Am J Pathol"},{"key":"2026032101051825300_bib30","first-page":"4140","article-title":"Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis","volume":"55","author":"Freeman","year":"1995","journal-title":"Cancer Res"},{"key":"2026032101051825300_bib31","doi-asserted-by":"crossref","first-page":"11418","DOI":"10.1073\/pnas.0610467104","article-title":"The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted","volume":"104","author":"Bonnet","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032101051825300_bib32","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1084\/jem.20071008","article-title":"Pulmonary arterial remodeling induced by a Th2 immune response","volume":"205","author":"Daley","year":"2008","journal-title":"J Exp Med"},{"key":"2026032101051825300_bib33","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.0105-2896.2006.00427.x","article-title":"Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease","volume":"212","author":"Sakaguchi","year":"2006","journal-title":"Immunol Rev"},{"key":"2026032101051825300_bib34","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1002\/1529-0131(200010)43:10<2178::AID-ANR5>3.0.CO;2-Z","article-title":"Decreased cellular activity and replicative capacity of osteoblastic cells isolated from the periarticular bone of rheumatoid arthritis patients compared with osteoarthritis patients","volume":"43","author":"Yudoh","year":"2000","journal-title":"Arthritis Rheum"},{"key":"2026032101051825300_bib35","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/j.0300-9475.2004.01370.x","article-title":"Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus","volume":"59","author":"Liu","year":"2004","journal-title":"Scand J Immunol"},{"key":"2026032101051825300_bib36","doi-asserted-by":"crossref","first-page":"649","DOI":"10.2174\/092986707780059599","article-title":"The Janus face of CD4+CD25+ regulatory T cells in cancer and autoimmunity","volume":"14","author":"Danese","year":"2007","journal-title":"Curr Med Chem"},{"key":"2026032101051825300_bib37","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1183\/09031936.06.00152705","article-title":"Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension","volume":"28","author":"Tamby","year":"2006","journal-title":"Eur Respir J"},{"key":"2026032101051825300_bib38","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1183\/09031936.05.00045705","article-title":"Autoimmunity and pulmonary hypertension: a perspective","volume":"26","author":"Nicolls","year":"2005","journal-title":"Eur Respir J"},{"key":"2026032101051825300_bib39","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1093\/intimm\/dxl024","article-title":"Melanoma-derived gangliosides impair migratory and antigen-presenting function of human epidermal Langerhans cells and induce their apoptosis","volume":"18","author":"Bennaceur","year":"2006","journal-title":"Int Immunol"},{"key":"2026032101051825300_bib40","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1161\/CIRCRESAHA.109.197533","article-title":"Inhibition of the SDF-1\/CXCR4 axis attenuates neonatal hypoxia-induced pulmonary hypertension","volume":"104","author":"Young","year":"2009","journal-title":"Circ Res"},{"key":"2026032101051825300_bib41","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1465-9921-12-21","article-title":"Effect of chemokine receptor CXCR4 on hypoxia-induced pulmonary hypertension and vascular remodeling in rats","volume":"12","author":"Yu","year":"2011","journal-title":"Respir Res"},{"key":"2026032101051825300_bib42","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1183\/09031936.00045710","article-title":"Targeting of c-kit+ haematopoietic progenitor cells prevents hypoxic pulmonary hypertension","volume":"37","author":"Gambaryan","year":"2011","journal-title":"Eur Respir J"},{"key":"2026032101051825300_bib43","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1158\/1078-0432.CCR-10-2636","article-title":"CXCL12 (SDF1alpha)-CXCR4\/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?","volume":"17","author":"Duda","year":"2011","journal-title":"Clin Cancer Res"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/186\/9\/897\/67247978\/ajrccm_186_9_897.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/186\/9\/897\/67247978\/ajrccm_186_9_897.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T05:05:29Z","timestamp":1774069529000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/186\/9\/897\/8507800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,11,1]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2012,11,1]]},"published-print":{"date-parts":[[2012,11,1]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201202-0335oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,11]]},"published":{"date-parts":[[2012,11,1]]}}}