TNFalpha inhibits apoptotic cell clearance in the lung, exacerbating acute inflammation

Efficient removal of apoptotic cells is essential for resolution of inflammation. Failure to clear dying cells can exacerbate lung injury and lead to persistent inflammation and autoimmunity. Here we show that TNFalpha blocks apoptotic cell clearance by alveolar macrophages and leads to proinflammat...

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Bibliographic Details
Published in:American journal of physiology. Lung cellular and molecular physiology 2009-10, Vol.297 (4), p.L586-L595
Main Authors: Borges, Valeria M, Vandivier, R William, McPhillips, Kathleen A, Kench, Jennifer A, Morimoto, Konosuke, Groshong, Steve D, Richens, Tiffany R, Graham, Brian B, Muldrow, Alaina M, Van Heule, Lea, Henson, Peter M, Janssen, William J
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Inflammation - etiology
Inflammation - physiopathology
Interleukin-10 - metabolism
Interleukin-6 - metabolism
Leukocytes - metabolism
Lipopolysaccharides - pharmacology
Lung - drug effects
Lung - metabolism
Lung - pathology
Macrophages, Alveolar - cytology
Macrophages, Alveolar - drug effects
Macrophages, Alveolar - metabolism
Mice
Mice, Inbred BALB C
Neutrophils - metabolism
Phagocytosis
Pneumonia - etiology
Pneumonia - physiopathology
Receptors, Tumor Necrosis Factor, Type I - physiology
Receptors, Tumor Necrosis Factor, Type II - physiology
Transforming Growth Factor beta - metabolism
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Efficient removal of apoptotic cells is essential for resolution of inflammation. Failure to clear dying cells can exacerbate lung injury and lead to persistent inflammation and autoimmunity. Here we show that TNFalpha blocks apoptotic cell clearance by alveolar macrophages and leads to proinflammatory responses in the lung. Compared with mice treated with intratracheal TNFalpha or exogenous apoptotic cells, mice treated with the combination of TNFalpha plus apoptotic cells demonstrated reduced apoptotic cell clearance from the lungs and increased recruitment of inflammatory leukocytes to the air spaces. Treatment with intratracheal TNFalpha had no effect on the removal of exogenous apoptotic cells from the lungs of TNFalpha receptor-1 (p55) and -2 (p75) double mutant mice and no effect on leukocyte recruitment. Bronchoalveolar lavage from mice treated with TNFalpha plus apoptotic cells contained increased levels of proinflammatory cytokines IL-6, KC, and MCP-1, but exhibited no change in levels of anti-inflammatory cytokines IL-10 and TGF-beta. Administration of TNFalpha plus apoptotic cells during LPS-induced lung injury augmented neutrophil accumulation and proinflammatory cytokine production. These findings suggest that the presence of TNFalpha in the lung can alter the response of phagocytes to apoptotic cells leading to inflammatory cell recruitment and proinflammatory mediator production.
ISSN:1522-1504
DOI:10.1152/ajplung.90569.2008