The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome

Crit Care Med. 1999 Feb;27(2):304-12. doi: 10.1097/00003246-199902000-00036.


Objectives: To determine the concentrations of proinflammatory mediators, collagenases, and procollagen type III peptides in undiluted pulmonary edema fluids and in plasma obtained in patients with early acute respiratory distress syndrome (ARDS) and in control patients with hydrostatic lung edema; and to assess the relationship between these inflammatory and profibrotic markers.

Design: A prospective, clinical study with measurements of inflammatory markers in pulmonary edema fluids and in paired plasma samples.

Setting: A medical intensive care unit.

Patients: Patients intubated with lung permeability (n = 23) and hydrostatic (n = 8) pulmonary edema were prospectively enrolled in the study. The severity of the disease at the time of intubation was assessed, using the Simplified Acute Physiological Score (SAPS) II and the Lung Injury Score (LIS).

Interventions: Plasma and undiluted edema fluids were obtained at the time of intubation with pulmonary edema requiring mechanical ventilation; and in some patients, a second edema fluid sample was collected a few hours later.

Measurements and main results: Proinflammatory activity, dependent on the presence of bioactive proinflammatory cytokines, interleukin (IL)-8, and neutrophil matrix metalloproteinase (MMP)-9 were significantly increased in ARDS fluids compared with plasma or control fluids from patients with congestive heart failure. In contrast, MMP-2, originating from lung cells other than phagocytes, was slightly increased in ARDS edema fluids compared with plasma, but similar to levels found in hydrostatic edema fluids. Proinflammatory activity was undetectable in plasma from ARDS patients. Levels of procollagen peptide III, a marker of collagen synthesis, were increased in permeability edema fluids compared with hydrostatic edema fluids or plasma, confirming that alveolar collagen synthesis begins very early and in parallel with acute inflammation in ARDS. Control patients with hydrostatic edema had similar SAPS II and LIS scores compared with ARDS patients.

Conclusions: These results strongly support the conclusion that during the early phase of ARDS, the lung is the site of an intense inflammatory process with sequential activation of cytokines, chemokines, and secretion of proteases, as well as concomitant collagen synthesis. The inflammation is mostly limited to the lung, with low levels of inflammatory mediators in the systemic circulation. Unlike clinical scoring systems (SAPS II and LIS), inflammatory markers differentiate patients with permeability and hydrostatic pulmonary edema.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Biomarkers / analysis
  • Body Fluids / chemistry
  • Collagenases / analysis
  • Fibrosis
  • Heart Failure / metabolism
  • Humans
  • Inflammation Mediators / analysis*
  • Interleukin-8 / analysis
  • Matrix Metalloproteinase 9
  • Middle Aged
  • Peptide Fragments / analysis
  • Procollagen / analysis
  • Prospective Studies
  • Pulmonary Alveoli / pathology*
  • Pulmonary Edema / metabolism
  • Random Allocation
  • Respiratory Distress Syndrome / metabolism*
  • Time Factors


  • Biomarkers
  • Inflammation Mediators
  • Interleukin-8
  • Peptide Fragments
  • Procollagen
  • procollagen Type III-N-terminal peptide
  • Collagenases
  • Matrix Metalloproteinase 9