Activity of lung neutrophils and matrix metalloproteinases in cyclophosphamide-treated mice with experimental sepsis.
Sepsis in patients receiving chemotherapy may result in acute respiratory distress syndrome, despite decreased number of blood neutrophils [polymorphonuclear neutrophils (PMNs)]. In the present study, we investigated the correlation of cyclophosphamide (CY)-induced neutropenia with the destructive potential of lung PMN in respect to formation of septic acute lung injury (ALI). Mice were treated with 250 mg/kg of CY or saline (control) and subjected to cecal ligation and puncture (CLP) or sham operation. ALI was verified by histological examination. Lung PMNs and matrix metalloproteinases (MMPs) were assessed by flow cytometry and gelatin zymography. CLP in CY-treated mice induced a typical lung injury. Despite profound neutropenia, CY treatment did not attenuate CLP-induced ALI. This might relate to only a partial suppression of PMN: CY has significantly reduced PMN influx into the lungs (P = 0.008) and suppressed their oxidative metabolism, but had no suppressive effect on degranulation (P = 0.227) and even induced MMP-9 activity (P = 0.0003). In CY-untreated animals, peak of CLP-induced ALI coincided with massive PMN influx (P = 0.013), their maximal degranulation (P = 0.014) and activation of lung MMP-9 (P = 0.002). These findings may indicate an important role of the residual lung PMN and activation of MMP-9 in septic lung injury during CY chemotherapy.
Hirsh
Mark
M
Department of Surgery A and The Laboratory for Shock and Trauma Research, The Bruce Rappaport Faculty of Medicine, Rambam Medical Center, Technion-Israel Institute of Technology, Haifa, Israel.
Carmel
Julie
J
Kaplan
Viktoria
V
Livne
Erella
E
Krausz
Michael M
MM
D000818:Animals; D017209:Apoptosis; D003520:Cyclophosphamide; D004789:Enzyme Activation; D007166:Immunosuppressive Agents; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology
D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D003520:Cyclophosphamide; D020782:Matrix Metalloproteinases