Proinflammatory response of alveolar epithelial cells is enhanced by alveolar macrophage-produced TNF-α during pulmonary ischemia-reperfusion injury

Ashish K. Sharma, Lucas G. Fernandez, Alaa S. Awad, Irving L. Kron, Victor E. Laubach

Research output: Contribution to journalArticle

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Abstract

Pulmonary ischemia-reperfusion (IR) injury entails acute activation of alveolar macrophages followed by neutrophil sequestration. Although proinflammatory cytokines and chemokines such as TNF-α and monocyte chemoattractant protein-1 (MCP-1) from macrophages are known to modulate acute IR injury, the contribution of alveolar epithelial cells to IR injury and their intercellular interactions with other cell types such as alveolar macrophages and neutrophils remain unclear. In this study, we tested the hypothesis that following IR, alveolar macrophage-produced TNF-α further induces alveolar epithelial cells to produce key chemokines that could then contribute to subsequent lung injury through the recruitment of neutrophils. Cultured RAW264.7 macrophages and MLE-12 alveolar epithelial cells were subjected to acute hypoxiareoxygenation (H/R) as an in vitro model of pulmonary IR. H/R (3 h/1 h) significantly induced KC, MCP-1, macrophage inflammatory protein-2 (MIP-2), RANTES, and IL-6 (but not TNF-α) by MLE-12 cells, whereas H/R induced TNF-α, MCP-1, RANTES, MIP-1α, and MIP-2 (but not KC) by RAW264.7 cells. These results were confirmed using primary murine alveolar macrophages and primary alveolar type II cells. Importantly, using macrophage and epithelial coculture methods, the specific production of TNF-α by H/R-exposed RAW264.7 cells significantly induced proinflammatory cytokine/chemokine expression (KC, MCP-1, MIP-2, RANTES, and IL-6) by MLE-12 cells. Collectively, these results demonstrate that alveolar type II cells, in conjunction with alveolar macrophage-produced TNF-α, contribute to the initiation of acute pulmonary IR injury via a proinflammatory cascade. The release of key chemokines, such as KC and MIP-2, by activated type II cells may thus significantly contribute to neutrophil sequestration during IR injury.

Original languageEnglish (US)
Pages (from-to)L105-L113
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume293
Issue number1
DOIs
StatePublished - Jul 1 2007

Fingerprint

Alveolar Epithelial Cells
Alveolar Macrophages
Reperfusion Injury
Chemokine CXCL2
Chemokine CCL2
Chemokines
Chemokine CCL5
Lung
Neutrophils
Macrophages
Reperfusion
Interleukin-6
Ischemia
Cytokines
Neutrophil Infiltration
Lung Injury
Coculture Techniques

All Science Journal Classification (ASJC) codes

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

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title = "Proinflammatory response of alveolar epithelial cells is enhanced by alveolar macrophage-produced TNF-α during pulmonary ischemia-reperfusion injury",
abstract = "Pulmonary ischemia-reperfusion (IR) injury entails acute activation of alveolar macrophages followed by neutrophil sequestration. Although proinflammatory cytokines and chemokines such as TNF-α and monocyte chemoattractant protein-1 (MCP-1) from macrophages are known to modulate acute IR injury, the contribution of alveolar epithelial cells to IR injury and their intercellular interactions with other cell types such as alveolar macrophages and neutrophils remain unclear. In this study, we tested the hypothesis that following IR, alveolar macrophage-produced TNF-α further induces alveolar epithelial cells to produce key chemokines that could then contribute to subsequent lung injury through the recruitment of neutrophils. Cultured RAW264.7 macrophages and MLE-12 alveolar epithelial cells were subjected to acute hypoxiareoxygenation (H/R) as an in vitro model of pulmonary IR. H/R (3 h/1 h) significantly induced KC, MCP-1, macrophage inflammatory protein-2 (MIP-2), RANTES, and IL-6 (but not TNF-α) by MLE-12 cells, whereas H/R induced TNF-α, MCP-1, RANTES, MIP-1α, and MIP-2 (but not KC) by RAW264.7 cells. These results were confirmed using primary murine alveolar macrophages and primary alveolar type II cells. Importantly, using macrophage and epithelial coculture methods, the specific production of TNF-α by H/R-exposed RAW264.7 cells significantly induced proinflammatory cytokine/chemokine expression (KC, MCP-1, MIP-2, RANTES, and IL-6) by MLE-12 cells. Collectively, these results demonstrate that alveolar type II cells, in conjunction with alveolar macrophage-produced TNF-α, contribute to the initiation of acute pulmonary IR injury via a proinflammatory cascade. The release of key chemokines, such as KC and MIP-2, by activated type II cells may thus significantly contribute to neutrophil sequestration during IR injury.",
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Proinflammatory response of alveolar epithelial cells is enhanced by alveolar macrophage-produced TNF-α during pulmonary ischemia-reperfusion injury. / Sharma, Ashish K.; Fernandez, Lucas G.; Awad, Alaa S.; Kron, Irving L.; Laubach, Victor E.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 293, No. 1, 01.07.2007, p. L105-L113.

Research output: Contribution to journalArticle

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T1 - Proinflammatory response of alveolar epithelial cells is enhanced by alveolar macrophage-produced TNF-α during pulmonary ischemia-reperfusion injury

AU - Sharma, Ashish K.

AU - Fernandez, Lucas G.

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AU - Kron, Irving L.

AU - Laubach, Victor E.

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AB - Pulmonary ischemia-reperfusion (IR) injury entails acute activation of alveolar macrophages followed by neutrophil sequestration. Although proinflammatory cytokines and chemokines such as TNF-α and monocyte chemoattractant protein-1 (MCP-1) from macrophages are known to modulate acute IR injury, the contribution of alveolar epithelial cells to IR injury and their intercellular interactions with other cell types such as alveolar macrophages and neutrophils remain unclear. In this study, we tested the hypothesis that following IR, alveolar macrophage-produced TNF-α further induces alveolar epithelial cells to produce key chemokines that could then contribute to subsequent lung injury through the recruitment of neutrophils. Cultured RAW264.7 macrophages and MLE-12 alveolar epithelial cells were subjected to acute hypoxiareoxygenation (H/R) as an in vitro model of pulmonary IR. H/R (3 h/1 h) significantly induced KC, MCP-1, macrophage inflammatory protein-2 (MIP-2), RANTES, and IL-6 (but not TNF-α) by MLE-12 cells, whereas H/R induced TNF-α, MCP-1, RANTES, MIP-1α, and MIP-2 (but not KC) by RAW264.7 cells. These results were confirmed using primary murine alveolar macrophages and primary alveolar type II cells. Importantly, using macrophage and epithelial coculture methods, the specific production of TNF-α by H/R-exposed RAW264.7 cells significantly induced proinflammatory cytokine/chemokine expression (KC, MCP-1, MIP-2, RANTES, and IL-6) by MLE-12 cells. Collectively, these results demonstrate that alveolar type II cells, in conjunction with alveolar macrophage-produced TNF-α, contribute to the initiation of acute pulmonary IR injury via a proinflammatory cascade. The release of key chemokines, such as KC and MIP-2, by activated type II cells may thus significantly contribute to neutrophil sequestration during IR injury.

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