Abstract | OBJECTIVE: DESIGN: Nonlethal closed-chest unilateral lung contusion was induced in a hypoxia reporter mouse model and type 2 cell-specific hypoxia-inducible factor-1α 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-1α conditional knockout mice were isolated and evaluated for proinflammatory cytokines following lung contusion. Finally, the role of nuclear factor-κB and interleukin-1β as intermediates in this interaction was studied. RESULTS: Lung contusion induced profound global hypoxia rapidly. Increased expression of hypoxia-inducible factor-1α 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-1β, 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-κB. Hypoxia-inducible factor-1α in lung epithelial cells was shown to regulate interleukin-1β promoter activity. CONCLUSION:
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Authors | Madathilparambil V Suresh, Sadeesh Kumar Ramakrishnan, Bivin Thomas, David Machado-Aranda, Yu Bi, Nicholas Talarico, Erik Anderson, Shah M Yatrik, Krishnan Raghavendran |
Journal | Critical care medicine
(Crit Care Med)
Vol. 42
Issue 10
Pg. e642-53
(Oct 2014)
ISSN: 1530-0293 [Electronic] United States |
PMID | 25014067
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Anti-Inflammatory Agents
- Cytokines
- Hif1a protein, mouse
- Hypoxia-Inducible Factor 1, alpha Subunit
- Acriflavine
- Doxycycline
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Topics |
- Acriflavine
(pharmacology)
- Animals
- Anti-Inflammatory Agents
(pharmacology)
- Contusions
(complications, metabolism)
- Cytokines
(metabolism)
- Disease Models, Animal
- Down-Regulation
- Doxycycline
(pharmacology)
- Hypoxia-Inducible Factor 1, alpha Subunit
(antagonists & inhibitors, physiology)
- Inflammation
(etiology, metabolism, physiopathology, prevention & control)
- Lung Injury
(complications, metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Pulmonary Alveoli
(cytology, metabolism)
- Respiratory Mucosa
(cytology, metabolism)
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