Induction of neutrophil apoptosis and secondary necrosis during endotoxin-induced pulmonary inflammation in mice.
The present study investigated the relationship between apoptotic and necrotic cell death and their role in pulmonary inflammatory response to endotoxin. Pulmonary administration of lipopolysaccharide (LPS) caused a rapid increase in the levels of pro-inflammatory cytokine TNF-alpha and inflammatory cell influx in the bronchoalveolar lavage (BAL) fluids. Control mice showed only resident alveolar macrophages with no apoptosis, whereas LPS-treated mice showed clear apoptosis of BAL cells. Microscopic studies confirmed the presence of apoptotic neutrophils and macrophages ingesting apoptotic bodies. The number of apoptotic neutrophils increased concomitantly with the increase in neutrophil influx which peaked 1 day after the treatment. However, necrosis was not detected at this early time, but increased subsequently and peaked at day 3. The levels of necrosis and apoptosis were both elevated and prolonged at high LPS doses. Treatment of mice with phosphatidylserine (PS)-containing liposome, known to inhibit macrophage phagocytosis of apoptotic cells, increased the level of apoptosis and necrosis caused by LPS, whereas control non-PS liposome or saline treatment had no effects. We conclude that necrosis occurs secondary to apoptosis in LPS-treated lung model and that this development is not the result of direct insult by LPS. Instead, our results and previous studies suggest that inefficient clearance of apoptotic cells by macrophages contributes, at least in part, to the levels of apoptosis and necrosis induced by LPS. Because necrosis is associated with cell damage and release of histotoxic contents, this development is likely to play a role in determining the severity and duration of lung toxicity induced by endotoxin.
Medan
Djordje
D
Department of Pharmaceutical Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia 26506, USA.
Wang
Liying
L
Yang
Xiaodong
X
Dokka
Sujatha
S
Castranova
Vincent
V
Rojanasakul
Yon
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004731:Endotoxins; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D009504:Neutrophils / Q000502:physiology*; D010718:Phosphatidylserines / Q000008:administration & dosage / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*
D004731:Endotoxins; D008070:Lipopolysaccharides; D008081:Liposomes; D010718:Phosphatidylserines