Abstract
Acute lung injury is a major complication of hemorrhagic shock and the required resuscitation with large volumes of crystalloid fluids and blood products. We previously identified a role of macrophage-derived chemokine (CCL22/MDC) pulmonary inflammation following hemorrhage and resuscitation. However, further details regarding the induction of CCL22/MDC and its precise role in pulmonary inflammation after trauma remain unknown. In the current study we used in vitro experiments with a murine alveolar macrophage cell line, as well as an in vivo mouse model of hemorrhage and resuscitation, to identify key regulators in CCL22/MDC production. We show that trauma induces expression of IFNγ, which leads to production of CCL22/MDC through a signaling mechanism involving p38 MAPK, NF-κB, JAK, and STAT-1. IFNγ also activates TNFα production by alveolar macrophages, potentiating CCL22/MDC production via an autocrine mechanism. Neutralization of IFNγ or TNFα with specific antibodies reduced histological signs of pulmonary injury after hemorrhage and reduced inflammatory cell infiltration into the lungs.
Keywords:
JAK; NF-κB; STAT-1; alveolar macrophages; p38 MAPK; pulmonary inflammation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antibodies, Neutralizing / pharmacology
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Autocrine Communication / genetics
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Cell Line
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Chemokine CCL2 / genetics*
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Chemokine CCL2 / metabolism
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Gene Expression Regulation
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Hemorrhage / genetics*
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Hemorrhage / metabolism
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Hemorrhage / physiopathology
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Humans
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Hypotension / genetics*
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Hypotension / metabolism
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Hypotension / physiopathology
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / genetics*
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Interferon-gamma / metabolism
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Janus Kinases / genetics
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Janus Kinases / metabolism
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Lung / metabolism
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Lung / physiopathology
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Macrophages, Alveolar / drug effects
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Macrophages, Alveolar / metabolism*
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Macrophages, Alveolar / pathology
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Male
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Mice
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Mice, Inbred C57BL
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Pneumonia / genetics*
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Pneumonia / metabolism
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Pneumonia / physiopathology
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Resuscitation / methods
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / metabolism
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Signal Transduction
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / genetics*
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antibodies, Neutralizing
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Ccl2 protein, mouse
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Chemokine CCL2
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NF-kappa B
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STAT1 Transcription Factor
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Stat1 protein, mouse
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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Janus Kinases
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p38 Mitogen-Activated Protein Kinases