title: Small airway remodeling in acute respiratory distress syndrome: a study in autopsy lung tissue.
abstract: BACKGROUND
  Airway dysfunction in patients with the Acute Respiratory Distress Syndrome (ARDS) is evidenced by expiratory flow limitation and dynamic hyperinflation. These functional alterations have been attributed to closure/obstruction of small airways. Airway morphological changes have been reported in experimental models of acute lung injury, characterized by epithelial necrosis and denudation in distal airways. To date, however, no study has focused on the morphological airway changes in lungs from human subjects with ARDS. The aim of this study is to evaluate structural and inflammatory changes in distal airways in ARDS patients.
  
  
  METHODS
  We retrospectively studied autopsy lung tissue from subjects who died with ARDS and from control subjects who died of non pulmonary causes. Using image analysis, we quantified the extension of epithelial changes (normal, abnormal and denudated epithelium expressed as percentages of the total epithelium length), bronchiolar inflammation, airway wall thickness, and extracellular matrix (ECM) protein content in distal airways. The Student's t-test or the Mann-Whitney test was used to compare data between the ARDS and control groups. Bonferroni adjustments were used for multiple tests. The association between morphological and clinical data was analyzed by Pearson rank test.
  
  
  RESULTS
  Thirty-one ARDS patients (A: PaO2/FiO2 ≤200, 45 ± 14 years, 16 males) and 11 controls (C: 52 ± 16 years, 7 males) were included in the study. ARDS airways showed a shorter extension of normal epithelium (A:32.9 ± 27.2%, C:76.7 ± 32.7%, P < 0.001), a larger extension of epithelium denudation (A:52.6 ± 35.2%, C:21.8 ± 32.1%, P < 0.01), increased airway inflammation (A:1(3), C:0(1), P = 0.03), higher airway wall thickness (A:138.7 ± 54.3 μm, C:86.4 ± 33.3 μm, P < 0.01), and higher airway content of collagen I, fibronectin, versican and matrix metalloproteinase-9 (MMP-9) compared to controls (P ≤0.03). The extension of normal epithelium showed a positive correlation with PaO2/FiO2 (r2 = 0.34; P = 0.02) and a negative correlation with plateau pressure (r2 = 0.27; P = 0.04). The extension of denuded epithelium showed a negative correlation with PaO2/FiO2 (r2 = 0.27; P = 0.04).
  
  
  CONCLUSIONS
  Structural changes in small airways of patients with ARDS were characterized by epithelial denudation, inflammation and airway wall thickening with ECM remodeling. These changes are likely to contribute to functional airway changes in patients with ARDS.
authors.affiliation: Department of Pathology, Experimental Air Pollution Laboratory-LIM05, Sao Paulo University Medical School, Av Dr, Arnaldo 455, São Paulo 01246-903, Brazil. maina_morales@yahoo.com.br
authors.forename: Maina M B
authors.initials: MM
authors.lastname: Morales
authors.forename: Ruy C
authors.initials: RC
authors.lastname: Pires-Neto
authors.forename: Nicole
authors.initials: N
authors.lastname: Inforsato
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lanças
authors.forename: Luiz F F
authors.initials: LF
authors.lastname: da Silva
authors.forename: Paulo H N
authors.initials: PH
authors.lastname: Saldiva
authors.forename: Thais
authors.initials: T
authors.lastname: Mauad
authors.forename: Carlos R R
authors.initials: CR
authors.lastname: Carvalho
authors.forename: Marcelo B P
authors.initials: MB
authors.lastname: Amato
authors.forename: Marisa
authors.initials: M
authors.lastname: Dolhnikoff
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000502:physiology*; D001344:Autopsy; D016022:Case-Control Studies; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012128:Respiratory Distress Syndrome / Q000503:physiopathology*; D012189:Retrospective Studies