title: Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis (IPF) is characterized by the insidious onset of dyspnea or cough. However, a subset of patients has a short duration of symptoms with rapid progression to end-stage disease. In this study, we evaluated clinical and molecular features of "rapid" and "slow" progressors with IPF.
  
  
  RESULTS
  26 patients with <6 months of symptoms before first presentation [rapid progressors] and 88 patients with >24 months of symptoms [slow progressors] were studied. Survival was analyzed by the Kaplan-Meyer method and proportional hazard's model. Lung microarrays and tissue proteins were measured in a subset of patients. No differences were found in age, physiologic impairment and bronchoalveolar lavage (BAL) cellular profile. There were more males (OR = 6.5; CI:1.4-29.5; p = 0.006) and smokers (OR = 3.04; CI:1.1-8.3; p = 0.04) in the rapid progressors group. Survival from the beginning of symptoms was significantly reduced in rapid progressors (HR = 9.0; CI:4.48-18.3; p<0.0001) and there was a tendency for decreased survival from the time of diagnosis (HR = 1.5; CI:0.81-2.87; p = 0.18). We identified 437 differentially expressed genes. Lungs of rapid progressors overexpressed genes involved in morphogenesis, oxidative stress, migration/proliferation, and genes from fibroblasts/smooth muscle cells. Upregulation of two of these genes, adenosine-2B receptor and prominin-1/CD133, was validated by immunohistochemistry and were expressed by alveolar epithelial cells. BAL from rapid progressors showed a >2-fold increase of active matrix metalloproteinase-9, and induced a higher fibroblast migration compared with slow progressors and controls [238+/-98% versus 123+/-29% (p<0.05) and 30+/-17% (p<0.01)].
  
  
  CONCLUSIONS
  A subgroup of IPF patients, predominantly smoking males, display an accelerated clinical course and have a gene expression pattern that is different from those with slower progression and longer survival. These findings highlight the variability in the progression of IPF, and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF.
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico. mselmanl@yahoo.com.mx
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.forename: Guillermo
authors.initials: G
authors.lastname: Carrillo
authors.forename: Andrea
authors.initials: A
authors.lastname: Estrada
authors.forename: Mayra
authors.initials: M
authors.lastname: Mejia
authors.forename: Carina
authors.initials: C
authors.lastname: Becerril
authors.forename: José
authors.initials: J
authors.lastname: Cisneros
authors.forename: Miguel
authors.initials: M
authors.lastname: Gaxiola
authors.forename: Rogelio
authors.initials: R
authors.lastname: Pérez-Padilla
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Thomas
authors.initials: T
authors.lastname: Richards
authors.forename: James
authors.initials: J
authors.lastname: Dauber
authors.forename: Talmadge E
authors.initials: TE
authors.lastname: King
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
mesh_terms: D000368:Aged; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000503:physiopathology*; D012129:Respiratory Function Tests; D015996:Survival Rate; D014158:Transcription, Genetic