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Alveolar macrophage depletion increases the severity of acute inflammation following nonlethal unilateral lung contusion in mice.

ABSTRACT: Lung contusion (LC) is a common injury resulting from blunt thoracic trauma. LC is an important risk factor for the development acute lung injury, adult respiratory distress syndrome, and ventilator-associated pneumonia, all of which increase mortality from trauma. LC produces a nonspecific immune cellular response. Neutrophil recruitment is known to increase the severity of inflammation during LC. However, the exact role of macrophages in modulating the response to LC has not been well described.We used a cortical contusion impactor to induce unilateral LC in mice. Thoracic micro computed tomographic scans of these animals were obtained to document radiologic changes over time following LC. To understand the role of macrophages during LC, liposomal clodronate was used to deplete macrophage levels before traumatic insult. Acute inflammatory attributes after LC were assessed, by measuring pressure-volume mechanics; quantifying bronchial alveolar lavage levels of leukocytes, albumin, and cytokines; and finally examining lung specimen histopathology at 5, 24, 48, and 72 hours after injury.After LC, alveolar macrophage numbers were significantly reduced and exhibited slowed recovery. Simultaneously, there was a significant increase in bronchial alveolar lavage neutrophil counts. The loss of macrophages could be attributed to both cellular apoptosis and necrosis. Pretreatment with clodronate increased the severity of lung inflammation as measured by worsened pulmonary compliance, increased lung permeability, amplification of neutrophil recruitment, and increases in early proinflammatory cytokine levels.The presence of regulatory alveolar macrophages plays an important role in the pathogenesis of acute inflammation following LC.

SUBMITTER: Machado-Aranda D

PROVIDER: S-EPMC4543300 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Alveolar macrophage depletion increases the severity of acute inflammation following nonlethal unilateral lung contusion in mice.

Machado-Aranda David D V Suresh Madathilparambil M Yu Bi B Dolgachev Vladislov V Hemmila Mark R MR Raghavendran Krishnan K

The journal of trauma and acute care surgery 20140401 4

<h4>Background</h4>Lung contusion (LC) is a common injury resulting from blunt thoracic trauma. LC is an important risk factor for the development acute lung injury, adult respiratory distress syndrome, and ventilator-associated pneumonia, all of which increase mortality from trauma. LC produces a nonspecific immune cellular response. Neutrophil recruitment is known to increase the severity of inflammation during LC. However, the exact role of macrophages in modulating the response to LC has not ...[more]

PMID: 24662861

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Project description:OBJECTIVE:Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. Hypoxia-inducible factor-1? is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension. We set to determine if hypoxia-inducible factor-1? plays a role in the pathogenesis of acute inflammatory response and injury in lung contusion. DESIGN:Nonlethal closed-chest unilateral lung contusion was induced in a hypoxia reporter mouse model and type 2 cell-specific hypoxia-inducible factor-1? conditional knockout mice. The mice were killed at 5-, 24-, 48-, and 72-hour time points, and the extent of systemic and tissue hypoxia was assessed. In addition, injury and inflammation were assessed by measuring bronchoalveolar lavage cells (flow cytometry and cytospin), albumin (permeability injury), and cytokines (inflammation). Isolated type 2 cells from the hypoxia-inducible factor-1? conditional knockout mice were isolated and evaluated for proinflammatory cytokines following lung contusion. Finally, the role of nuclear factor-?B and interleukin-1? as intermediates in this interaction was studied. RESULTS:Lung contusion induced profound global hypoxia rapidly. Increased expression of hypoxia-inducible factor-1? from lung samples was observed as early as 60 minutes, following the insult. The extent of lung injury following lung contusion was significantly reduced in conditional knockout mice at all the time points, when compared with the wild-type littermate mice. Release of proinflammatory cytokines, such as interleukin-1?, interleukin-6, macrophage inflammatory protein-2, and keratinocyte chemoattractant, was significantly lower in conditional knockout mice. These actions are in part mediated through nuclear factor-?B. Hypoxia-inducible factor-1? in lung epithelial cells was shown to regulate interleukin-1? promoter activity. CONCLUSION:Activation of hypoxia-inducible factor-1? in type 2 cell is a major driver of acute inflammation following lung contusion.

Dataset Information

Alveolar macrophage depletion increases the severity of acute inflammation following nonlethal unilateral lung contusion in mice.

Publications

Alveolar macrophage depletion increases the severity of acute inflammation following nonlethal unilateral lung contusion in mice.

Similar Datasets

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