title: Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  There is microscopic spatial and temporal heterogeneity of pathological changes in idiopathic pulmonary fibrosis (IPF) lung tissue, which may relate to heterogeneity in pathophysiological mediators of disease and clinical progression. We assessed relationships between gene expression patterns, pathological features, and systemic biomarkers to identify biomarkers that reflect the aggregate disease burden in patients with IPF.
  
  
  METHODS
  Gene expression microarrays (N=40 IPF; 8 controls) and immunohistochemical analyses (N=22 IPF; 8 controls) of lung biopsies. Clinical characterisation and blood biomarker levels of MMP3 and CXCL13 in a separate cohort of patients with IPF (N=80).
  
  
  RESULTS
  2940 genes were significantly differentially expressed between IPF and control samples (|fold change| >1.5, p<0.05). Two clusters of co-regulated genes related to bronchiolar epithelium or lymphoid aggregates exhibited substantial heterogeneity within the IPF population. Gene expression in bronchiolar and lymphoid clusters corresponded to the extent of bronchiolisation and lymphoid aggregates determined by immunohistochemistry in adjacent tissue sections. Elevated serum levels of MMP3, encoded in the bronchiolar cluster, and CXCL13, encoded in the lymphoid cluster, corresponded to disease severity and shortened survival time (p<10(-7) for MMP3 and p<10(-5) for CXCL13; Cox proportional hazards model).
  
  
  CONCLUSIONS
  Microscopic pathological heterogeneity in IPF lung tissue corresponds to specific gene expression patterns related to bronchiolisation and lymphoid aggregates. MMP3 and CXCL13 are systemic biomarkers that reflect the aggregate burden of these pathological features across total lung tissue. These biomarkers may have clinical utility as prognostic and/or surrogate biomarkers of disease activity in interventional studies in IPF.
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Daryle J
authors.initials: DJ
authors.lastname: DePianto
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA Novartis Institutes for Biomedical Research, Emeryville, California, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Chandriani
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Abbas
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Guiquan
authors.initials: G
authors.lastname: Jia
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Elsa N
authors.initials: EN
authors.lastname: N'Diaye
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Caplazi
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kauder
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA Gilead Sciences, Foster City, California, USA.
authors.forename: Satyajit K
authors.initials: SK
authors.lastname: Karnik
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Ha
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Department of Surgery, University of California, San Francisco, California, USA.
authors.forename: Jasleen
authors.initials: J
authors.lastname: Kukreja
authors.affiliation: Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Harold R
authors.initials: HR
authors.lastname: Collard
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Jackson G
authors.initials: JG
authors.lastname: Egen
authors.affiliation: Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
authors.affiliation: Genentech Research and Early Development, South San Francisco, California, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Arron
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes; D054382:Chemokine CXCL13 / Q000096:biosynthesis / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D012720:Severity of Illness Index
chemical_list: C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3
keywords: Idiopathic pulmonary fibrosis