Association of Interferon- and Transforming Growth Factor beta-Regulated Genes and Macrophage Activation With Systemic Sclerosis-Related Progressive Lung Fibrosis

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorCHRISTMANN, Romy B.
dc.contributor.authorSAMPAIO-BARROS, Percival
dc.contributor.authorSTIFANO, Giuseppina
dc.contributor.authorBORGES, Claudia L.
dc.contributor.authorCARVALHO, Carlos R. de
dc.contributor.authorKAIRALLA, Ronaldo
dc.contributor.authorPARRA, Edwin R.
dc.contributor.authorSPIRA, Avrum
dc.contributor.authorSIMMS, Robert
dc.contributor.authorCAPELLOZZI, Vera L.
dc.contributor.authorLAFYATIS, Robert
dc.date.accessioned2014-09-30T14:55:05Z
dc.date.available2014-09-30T14:55:05Z
dc.date.issued2014
dc.description.abstractObjective. Systemic sclerosis (SSc)-related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc-related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease. Methods. Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc-related ILD and in 4 controls. High-resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2-3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein. Results. Lung microarray data distinguished patients with SSc-related ILD from healthy controls. In the lungs of patients with SSc-related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor beta (TGF beta)- and interferon (IFN)-regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < -0.1), including IFN and macrophage markers, chemokines, and heat-shock proteins. Conclusion. These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGF beta- and IFN-regulated genes.
dc.description.indexWoS
dc.description.sponsorshipNIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] Center of Research Translation [1-P50-AR-060780-01]
dc.description.sponsorshipNIH (NIAMS) [2-R01-AR-051089-06A1]
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil (CNPq)
dc.identifier.citationARTHRITIS & RHEUMATOLOGY, v.66, n.3, p.714-725, 2014
dc.identifier.doi10.1002/art.38288
dc.identifier.eissn2326-5205
dc.identifier.issn2326-5191
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/7785
dc.language.isoeng
dc.publisherWILEY-BLACKWELL
dc.relation.ispartofArthritis & Rheumatology
dc.rightsrestrictedAccess
dc.rights.holderCopyright WILEY-BLACKWELL
dc.subject.otheridiopathic pulmonary-fibrosis
dc.subject.othercentrilobular fibrosis
dc.subject.othercirculating monocytes
dc.subject.otherscleroderma
dc.subject.otherdisease
dc.subject.otherexpression
dc.subject.otherchemokine
dc.subject.otheralpha
dc.subject.othersubsets
dc.subject.otherdeath
dc.subject.wosRheumatology
dc.titleAssociation of Interferon- and Transforming Growth Factor beta-Regulated Genes and Macrophage Activation With Systemic Sclerosis-Related Progressive Lung Fibrosis
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryisous
hcfmusp.author.externalCHRISTMANN, Romy B.:Boston Univ, Sch Med, Boston, MA 02118 USA; Univ Sao Paulo, Sch Med, Sao Paulo, Brazil
hcfmusp.author.externalSTIFANO, Giuseppina:Boston Univ, Sch Med, Boston, MA 02118 USA
hcfmusp.author.externalBORGES, Claudia L.:Univ Sao Luis do Maranhao, CEUMA, Sao Luis, MA, Brazil
hcfmusp.author.externalCARVALHO, Carlos R. de:Univ Sao Luis do Maranhao, CEUMA, Sao Luis, MA, Brazil
hcfmusp.author.externalKAIRALLA, Ronaldo:Univ Sao Luis do Maranhao, CEUMA, Sao Luis, MA, Brazil
hcfmusp.author.externalPARRA, Edwin R.:Univ Sao Luis do Maranhao, CEUMA, Sao Luis, MA, Brazil
hcfmusp.author.externalSPIRA, Avrum:Boston Univ, Sch Med, Boston, MA 02118 USA
hcfmusp.author.externalSIMMS, Robert:Boston Univ, Sch Med, Boston, MA 02118 USA
hcfmusp.author.externalCAPELLOZZI, Vera L.:Univ Sao Luis do Maranhao, CEUMA, Sao Luis, MA, Brazil
hcfmusp.author.externalLAFYATIS, Robert:Boston Univ, Sch Med, Boston, MA 02118 USA
hcfmusp.citation.scopus167
hcfmusp.contributor.author-fmusphcPERCIVAL DEGRAVA SAMPAIO BARROS
hcfmusp.description.beginpage714
hcfmusp.description.endpage725
hcfmusp.description.issue3
hcfmusp.description.volume66
hcfmusp.origemWOS
hcfmusp.origem.pubmed24574232
hcfmusp.origem.scopus2-s2.0-84896287076
hcfmusp.origem.wosWOS:000337359400028
hcfmusp.publisher.cityHOBOKEN
hcfmusp.publisher.countryUSA
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hcfmusp.remissive.sponsorshipCNPq
hcfmusp.remissive.sponsorshipFAPESP
hcfmusp.remissive.sponsorshipNIH
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