title: Association of Interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis.
abstract: OBJECTIVE
  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 β (TGFβ)- 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.
  
  
  CONCLUSIONS
  These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGFβ- and IFN-regulated genes.
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts; University of Sao Paulo School of Medicine, Sao Paulo, Brazil.
authors.forename: Romy B
authors.initials: RB
authors.lastname: Christmann
authors.forename: Percival
authors.initials: P
authors.lastname: Sampaio-Barros
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Stifano
authors.forename: Claudia L
authors.initials: CL
authors.lastname: Borges
authors.forename: Carlos R
authors.initials: CR
authors.lastname: de Carvalho
authors.forename: Ronaldo
authors.initials: R
authors.lastname: Kairalla
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Parra
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.forename: Robert
authors.initials: R
authors.lastname: Simms
authors.forename: Vera L
authors.initials: VL
authors.lastname: Capellozzi
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000941:Antigens / Q000235:genetics / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008262:Macrophage Activation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012129:Respiratory Function Tests; D012595:Scleroderma, Systemic / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: D000941:Antigens; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C111792:CCL18 protein, human; D000098902:CD163 Antigen; D019742:Chemokines, CC; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D003598:Cytoskeletal Proteins; C065888:IFI44 protein, human; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase