Upregulation of Two Death Pathways of Perforin/Granzyme and FasL/Fas in Septic Acute Respiratory Distress Syndrome

Abstract

Accumulation and activation of inflammatory cells in the lung characterize the acute respiratory distress syndrome (ARDS). However, the precise mechanism for lung epithelial and endothelial cell damage remains unknown. Based on evidence that rapid apoptosis caused by CD8(+) cytolytic T cells can induce pathological cell death, we hypothesized that this mechanism may also participate in the acute lung injury, and attempted to evaluate apoptosis-related factors in bronchoalveolar lavage fluid (BALF) from ARDS patients. Quantitative polymerase chain reaction (PCR) analysis revealed that the messenger ribonucleic acids (mRNAs) for several apoptosis molecules, such as perforin, granzyme A, granzyme B, FasL, and Fas were highly upregulated in the acute phase of ARDS following sepsis. In contrast, low or negligible mRNA expression of these molecules was detected in patients with normal lung function, in septic patients without lung injury (septic non-ARDS), and in patients in the late phase of septic ARDS (late ARDS). While the genes of the classic proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8, and inducible nitric oxide synthase (iNOS) were upregulated in septic non-ARDS or late ARDS patients, expressions of these genes in the acute phase of septic ARDS were most distinct. The immunofluorescence flow cytometry showed that only the lymphocyte population in BALF from acute phase of septic ARDS patients expressed perforin and granzyme. The level of soluble FasL in the BALF increased only in the acute ARDS patients. These results thus suggested that the dual apoptosis pathway, perforin/granzyme and FasL/Fas system, is likely to be another participant for the pathogenesis of acute lung injury.

Loss of Extracellular Superoxide Dismutase Leads to Acute Lung Damage in the Presence of Ambient Air

“…41 These investigators have also shown high levels of mRNA for several products of CD8 ϩ T cells, including granzymes A and B, perforin, Fas, and Fas ligand in the bronchoalveolar fluid of patients during the acute phase of lung injury. 42 These molecules participate in apoptotic cytotoxicity induced by CD8 cells and could contribute to lung injury. The large accumulation of granulocytes occurs in numerous types in acute lung injury.…”

Activated T killer cells induce apoptosis in lung epithelial cells and the release of pro‐inflammatory cytokine TNF‐α

“…In the acute phase (within 24 h of diagnosis) of septic ARDS patients, expression of perforin and granzyme B on lymphocytes and the presence of high levels of soluble CD95 ligand (CD95L) in the bronchoalveolar lavage fluid (BALF) have been detected. These findings are absent in late phase or septic non-ARDS patients [16]. Such reports suggest the participation of CD95/CD95L-and perforin/ granzyme-mediated pathways in lung epithelial cell injury in ARDS and interstitial pneumonia.…”

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.…”