Direct evidence of secondary necrosis of neutrophils during intense lung inflammation

¹ Dept. Experimental Medical Science, Div. Vascular and Airway Research, Lund University, Lund, Sweden

^* To whom correspondence should be addressed. E-mail: Kristina.Rydell-Tormanen{at}med.lu.se.

	Abstract

Several pulmonary inflammatory conditions are characterized by infiltration of neutrophils. Normally neutrophils are silently removed by apoptosis followed by Phagocytosis. However, if phagocytosis fails, apoptotic cells undergo secondary necrosis. Recent findings of increased levels of the pan-necrosis marker lactatedehydrogenase in bronchoalveolar lavage from lipopolysaccharide-exposed mice, implies potential involvement of secondary necrosis. Using a similar model, we sought to identify the source of lactatedehydrogenase, and search for direct histological evidence of secondary necrosis. Lipopolysaccharide was administered to the lungs of BALB/c mice, and bronchoalveolar lavage and tissue samples were collected 4, 12, 24, 36, 48, 60 and 72 h after administration. Lipopolysaccharide induced a patchy neutrophil-rich lung inflammation, with areas of intense inflammation and neutrophil infiltration, where the numbers of TUNEL-positive neutrophils were increased at 12 h and onwards. Lavage levels of neutrophils and lactatedehydrogenase increased significantly at 4 and 24 h respectively. Detailed electron microscopic assessment of neutrophil activation and death modes, revealed that up to 14% of the neutrophils were undergoing secondary necrosis, whereas few apoptotic or primary necrotic structural cells were rarely found. In summary, this study provides direct evidence that secondary necrosis of neutrophils is a common process during intense lung inflammation and this implies that neutrophil apoptosis may cause rather than resolve airway inflammation.

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