Fas and Fas Ligand Are Up-Regulated in Pulmonary Edema Fluid and Lung Tissue of Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome

Abstract

Apoptosis mediated by Fas/Fas ligand (FasL) interaction has been implicated in human disease processes, including pulmonary disorders. However, the role of the Fas/FasL system in acute lung injury (ALI) and in the acute respiratory distress syndrome (ARDS) is poorly defined. Accordingly, we investigated both the soluble and cellular expression of the Fas/FasL system in patients with ALI or ARDS. The major findings are summarized as follows. First, the soluble expression of the Fas/FasL system was assessed in undiluted pulmonary edema fluid and simultaneous plasma. Pulmonary edema fluid obtained from patients with ALI or ARDS (n = 51) had significantly higher concentrations of both soluble Fas (27 ng/ml; median; P < 0.05) and soluble FasL (0.125 ng/ml; P < 0.05) compared to control patients with hydrostatic pulmonary edema (n = 40; soluble Fas, 12 ng/ml; soluble FasL, 0.080 ng/ml). In addition, the concentrations of both soluble Fas and soluble FasL were significantly higher in the pulmonary edema fluid of the patients with ALI or ARDS compared to simultaneous plasma samples (soluble Fas, 16 ng/ml; soluble FasL, 0.058 ng/ml; P < 0.05), indicating local release in the lung. Higher soluble Fas concentrations were associated with worse clinical outcomes. Second, cellular expression of the Fas/FasL system was assessed by semiquantitative immunofluorescence microscopy in lung tissue obtained at autopsy from a different set of patients. Both Fas and FasL were immunolocalized to a greater extent in the patients who died with ALI or ARDS (n = 10) than in the patients who died without pulmonary disease (n = 10). Both proteins were co-expressed by epithelial cells that lined the alveolar walls, as well as by inflammatory cells and sloughed epithelial cells that were located in the air spaces. Semiquantitative immunohistochemistry showed that markers of apoptosis (terminal dUTP nick-end labeling, caspase-3, Bax, and p53) were more prevalent in alveolar wall cells from the patients who died with ALI or ARDS compared to the patients who died without pulmonary disease. These findings indicate that alveolar epithelial injury in humans with ALI or ARDS is in part associated with local up-regulation of the Fas/FasL system and activation of the apoptotic cascade in the epithelial cells that line the alveolar air spaces.

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

“…Alternatively, a separate internal or mitochondrial pathway can mediate apoptosis via cytochrome c and caspase activation. Lung tissue from both humans with ALI and animal models of ALI demonstrate activation of apoptotic pathways in the alveolar epithelium [22,23]. Matute-Bello and colleagues reported that bronchoalveolar fluid from patients with ALI contained soluble Fas ligand (sFasL), and the concentration of sFasL at the onset of ARDS was significantly higher in patients who died [24].…”

Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome

“…The Fas-FasL system is thought to play a role in epithelial apoptosis in ARDS on the basis that bronchoalveolar lavage (BAL) fluids obtained from ARDS patients contain soluble Fas and FasL and induce apoptosis in lung epithelial cell line. [5][6][7][8] Involvement of BAX, a homolog of Bcl-2 and its likely proapoptotic effect on type II pneumocytes was suggested in studies of diffuse alveolar damage. 9,10 Neutrophils were found to accumulate at inflammatory sites in the lung, in pulmonary edema fluid and BAL fluid from patients with ARDS.…”

A Role for Forkhead Box A1 in Acute Lung Injury

“…The epithelial hypothesis suggests that the epithelial injury that occurs during ALI is associated with apoptotic death of alveolar epithelial cells and predicts that anti-apoptotic therapeutic agents may be beneficial in preventing or treating ALI [13,34,35]. Our results showed that caspase-3 activity was increased in lung tissue following challenge with OA.…”

“…Bardales et al [39] reported that alveolar pneumocytes isolated from humans with ALI demonstrate upregulation of the pro-apoptotic protein, Bax [39]. In addition, several lines of evidence implicate Fas and Fas ligand in alveolar epithelial cell apoptosis during ALI [13,14,34,[41][42][43]. However, this is the first investigation into the role of FoxA1 in apoptosis during ALI.…”

“…Many studies suggest that the epithelial injury that occurs during ALI/ARDS may be attributed to apoptosis of alveolar epithelial cells in response to soluble mediators such as Fas ligand, and that blockade of such mediators may be beneficial in preventing or treating ALI/ARDS [13,14].…”