Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury

Abstract

-The alveolar fibrinolytic system is altered in acute lung injury (ALI). Levels of the fibrinolytic protease inhibitor, plasminogen activator inhibitor-1 (PAI-1), are too low in bronchoalveolar lavage to address its prognostic significance. This study was performed to assess whether PAI-1 antigen in undiluted pulmonary edema fluid levels can identify patients with ALI and predict their outcome. PAI-1 antigen levels in both plasma and edema fluid were higher in ALI compared with hydrostatic edema, and edema fluid PAI-1 values identified those with ALI with high sensitivity and specificity. Both the high plasma and edema fluid PAI-1 antigen values were associated with a higher mortality rate and fewer days of unassisted ventilation in patients with ALI. Differences in PAI-1 activity were concordant with levels of PAI-1 antigen. Although the fibrinderived alveolar D-dimer levels were strikingly similar in both groups, ALI patients had a higher relative proportion of D-monomer. In conclusion, PAI-1 levels in edema fluid and plasma identify those with ALI that have a poor prognosis. The data indicate that fibrin turnover in early ALI is a consequence of a rapid fibrinogen influx and fractional fibrinolytic inhibition.fibrinolysis; prognosis CURRENT ESTIMATES INDICATE that the incidence of acute lung injury (ALI) is 20-75 per 100,000 persons, with a mortality rate of 20-60% (48). Prior studies that have attempted to identify prognostic markers in bronchoalveolar lavage (BAL) fluid obtained from patients with ALI in the first several days after intubation have met with only modest success (7,8,15,37,38). Several obstacles exist in identifying valuable and reliable prognostic markers in ALI. For instance, it is clear that the lung inflammation evolves rapidly in ALI, making the timing of the analysis crucial. Second, there are both soluble activators and inhibitors for numerous cytokines/chemokines in the inflammatory milieu. Third, the BAL procedure itself dilutes the alveolar contents 100-fold, making it difficult to quantify potentially useful markers of ALI. Finally, the heterogeneity of underlying diseases and choice of control groups add to the difficulty in extrapolating the findings to disease pathobiology. We have overcome some of these obstacles by utilizing undiluted pulmonary edema fluid, not BAL fluid, that was obtained from patients with clinical ALI and well-defined hydrostatic pulmonary edema (HYDRO) controls within hours of intubation and initiation of mechanical ventilation.ALI is characterized by the deposition of fibrin in the alveolar space. Deposition of fibrin in the alveolar space is the net result of an alteration in the balance of coagulation and fibrinolytic proteases [plasmin and urokinase type plasminogen activators (u-PA)] and antiproteases [plasminogen activator inhibitor-1 (PAI-1) and ␣ 2 -antiplasmin] and the availability of plasmaderived fibrinogen (31,35). Upon fibrinogen influx into the alveolar compartment, coagulation/fibrinolysis proteases/antiproteases act to generate insoluble cr...

Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury*

“…Protein C was measured using a commercially available ELISA from Helena Laboratories (Beaumont, TX), as described previously (18). PAI-1 was measured using a commercially available ELISA from American Diagnostica (Stamford, CT), as previously described (19). Measurements were made in available samples from the cohort; the number of available measurements differed by biomarker, but ranged from 361 to 755.…”

Tissue plasminogen activator attenuates ventilator-induced lung injury in rats

“…Studies of animal models of VILI showed that high tidal volume ventilation increases alveolar fibrin deposition and systemic PAI-1 activity while lungprotective mechanical ventilation decreases BALF levels of PAI-1, attenuates coagulation, and enhances fibrinolysis [14,21] . Although aerosol administration offers the theoretical advantage of the lungs receiving high concentrations of tPA, we chose intravenous administration because intra-alveolar and intravascular fibrin deposition and high systemic PAI-1 levels are frequently found in the setting of acute lung injury or VILI [5,15] . Intraperitoneal tPA lavage could also reduce intraabdominal PAI-1 concentrations in experimental peritonitis [20] .…”

“…High pulmonary and systemic PAI-1 levels and increased alveolar fibrin deposition are features of animal models of VILI [14] . Increased plasma levels of PAI-1 are associated with adverse clinical outcomes and increased mortality in adults with acute lung injury [15] . tPA is responsible for fibrin degradation via the activation of plasminogen and has been used for thrombolysis in patients with acute myocardial infarction [16] .…”

Functional Genomic Insights into Acute Lung Injury: Role of Ventilators and Mechanical Stress

“…Ontology analysis of the candidate genes demonstrates that the major mechanical stretch-related ALI biological process was blood coagulation with genes in this ontology including fibrinogen A, coagulation factor III, plasminogen activator, urokinase receptor (uPAR), tissue factor, and PAI-1 ( Figure 3). Many of these same genes have been implicated elsewhere as potential candidate genes in ALI (13,28,29) and in VALI (30,31). In addition to coagulation, there was prominent representation of genes involved in innate immunity (MIF, CD14, TNF, IL-1RA, C5aR, IL-6).…”

“…Despite the evidence from association-based studies suggesting that genetic variation contributes to ALI susceptibility and severity (5)(6)(7)(8)(9)(10)(11)(12)(13), the genetic basis of ALI remains incompletely understood. Multiple factors contribute to the difficulty in defining the exact nature of genetic factors relevant to ALI.…”