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* From the University of California, San Francisco, Cardiovascular Research Institute, San Francisco, CA. Supported by grant NIH HL51586.
Correspondence to: Lorraine B. Ware, MD, Cardiovascular Research Institute, Box 0130, 505 Parnassus Ave, San Francisco, CA 94143-0130; e-mail: lware{at}itsa.ucsf.edu
Injury to the lung endothelial barrier initiates the accumulation of protein-rich edema fluid in the alveolar space in patients with acute lung injury (ALI). However, recent experimental and clinical data suggest that injury to both the endothelial and epithelial barriers is important to the development and resolution of ALI.1 2 The recognition of these two potential sites of injury stimulated a study of two biological markers: von Willebrand factor antigen (vWf-Ag) and soluble intercellular adhesion molecule-1 (sICAM-1). vWf-Ag, a high-molecular-weight antigen, is a marker of endothelial activation and injury that we have previously found to be prognostic in patients with sepsis at risk for developing ALI.3 By contrast, sICAM-1, a low-molecular-weight adhesion molecule, is both an epithelial and endothelial marker; in addition to being identified on the alveolar capillary endothelium, it is found in high concentrations on the alveolar epithelium4 5 and is released in soluble form into the alveolar space in the setting of lung injury.4 6
The objectives of the current study were first to measure levels of sICAM-1 and vWf-Ag in the plasma and pulmonary edema fluid of patients with established ALI, using patients with hydrostatic pulmonary edema as a control population for comparison. Second, the levels were compared with physiologically and clinically relevant outcomes, including days of mechanical ventilation and net alveolar fluid clearance. We hypothesized that sICAM-1, a combined endothelial and epithelial marker, would have clinical value.
Materials and Methods
Patient Selection
Thirty-one intubated, mechanically ventilated patients
with acute pulmonary edema were identified over a 2-year period
(approved by the University of California San Francisco Committee on
Human Research). Medical records were reviewed, and clinical data were
obtained, including the cause of pulmonary edema, hemodynamic data, and
the duration of ventilation. Based on clinical history, the initial
edema fluid to plasma protein ratio, and hemodynamic data, there were 9
patients with hydrostatic edema and 18 patients with ALI. Four patients
could not be definitively categorized and were excluded from the
analysis. For each patient, severity of respiratory failure was
assessed by the duration of unassisted ventilation in a 28-day period.
Sampling of Pulmonary Edema Fluid
Undiluted pulmonary edema fluid and plasma were sampled
simultaneously in each patient within 1 h of tracheal intubation,
as previously described.2
Briefly, a 14F suction catheter
was passed through the endotracheal tube and wedged in a distal
airspace. Gentle suction was applied to collect undiluted alveolar
edema fluid. Protein concentration was measured by the Biuret
method.2
7
The initial edema fluid to plasma protein
ratio, an index of alveolar capillary membrane permeability, was
calculated for all patients. Pulmonary edema fluid was sampled hourly
for up to 6 h. A net rate of alveolar fluid clearance was
calculated based on change in protein concentration in serial samples.
Measurement of sICAM-1 and vWf-Ag Levels
Levels of sICAM-1 and vWf-Ag were measured in duplicate in all
edema fluid and plasma samples by commercially available enzyme-linked
immunosorbent assays (sICAM-1 kit from BioSource International,
Camarillo, CA, vWf-Ag kit from Diagnostica Stago, Asnières,
France).
Statistical Analysis
Comparison of sICAM-1 and vWf-Ag levels in plasma to edema fluid
and between hydrostatic and ALI patients was made with an unpaired
t test. A p value of < 0.05 was considered significant.
2 analysis was used to compare levels of vWf-Ag and
sICAM-1 to duration of unassisted ventilation and presence or absence
of alveolar fluid clearance.
Results
As shown in Table 1 , levels of vWf-Ag were consistently lower in the pulmonary edema fluid compared with plasma in all patients. Patients with ALI had sixfold higher edema fluid levels than patients with hydrostatic pulmonary edema (p < 0.05), suggesting that vWf-Ag leaks from the plasma to the alveoli in ALI patients primarily from an increase in lung endothelial permeability.
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When compared with clinical and physiologic correlates in ALI patients, sICAM-1 levels tended to be higher in patients with no net alveolar fluid clearance (p = 0.08), and were higher in patients with more severe respiratory failure, as measured by fewer days of unassisted ventilation (p < 0.05).
Discussion
A variety of biological markers have been studied in ALI, including cytokines, growth factors, metalloproteinases, markers of collagen synthesis, and markers of endothelial injury.8 To date, however, relatively few markers have been identified that reliably predict outcome in patients with established ALI. Furthermore, despite the diversity of markers that have been studied, there have been almost no studies of markers of alveolar epithelial injury, largely due to the current lack of lung epithelial-specific markers. In recent years, ICAM-1, an important adhesion molecule that mediates leukocyte-endothelial interaction, has been identified on the alveolar epithelium.4 5 While its function is unclear, it has been postulated to play a role in regulation of alveolar macrophages.9 10 Because of its location on both the alveolar capillary endothelium and alveolar epithelium, we hypothesized that direct measurement of sICAM-1 in the alveolar space of patients with ALI would be a useful marker of severity of ALI.
We therefore measured levels of two biological markers, vWf-Ag, an endothelial marker, and sICAM-1, an endothelial and epithelial marker, in both the plasma and pulmonary edema fluid from patients with ALI and hydrostatic pulmonary edema. The findings can be summarized as follows. vWf-Ag, the endothelial marker, was higher in the pulmonary edema fluid of ALI patients than hydrostatic patients, but was lower than plasma concentration in both groups. By contrast, sICAM-1, the endothelial and epithelial marker, was elevated in edema fluid from ALI patients, much higher than simultaneous plasma levels, and much higher than levels in the control group of patients with pulmonary edema from pure hydrostatic causes. Furthermore, high edema fluid levels of sICAM-1 were correlated with a longer duration of mechanical ventilation (as measured by days of unassisted ventilation) and were associated with impaired alveolar fluid clearance.
The exact source of the high levels of sICAM-1 measured in pulmonary edema fluid of ALI patients is unclear, but the elevated levels suggest local release in the lung, rather than leakage from the plasma. In experimental studies, the membrane-bound form of ICAM-1 has been identified in high levels on alveolar type I cells, with lower levels on alveolar macrophages and endothelial cells.4 5 In the setting of injury, ICAM-1 is induced on alveolar type II cells11 and is released in soluble form into the alveolar space.4 6 In the current study, the association of high edema fluid sICAM-1 levels with absent alveolar epithelial fluid clearance suggests that the sICAM-1 is released from the damaged alveolar epithelium. However, release from alveolar macrophages or the capillary endothelium probably occurs as well.
In conclusion, sICAM-1 in pulmonary edema fluid from ALI patients may be a valuable marker for both the biological and clinical severity of ALI.
References
and IFN
: the inducibility of specific cell ICAM-1 in vivo. Am J Respir Cell Mol Biol 15,540-550
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