HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Activation of hypoxia-inducible factor-1α in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion.

AbstractOBJECTIVE:
Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. Hypoxia-inducible factor-1α 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-1α 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-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:
Activation of hypoxia-inducible factor-1α in type 2 cell is a major driver of acute inflammation following lung contusion.
AuthorsMadathilparambil V Suresh, Sadeesh Kumar Ramakrishnan, Bivin Thomas, David Machado-Aranda, Yu Bi, Nicholas Talarico, Erik Anderson, Shah M Yatrik, Krishnan Raghavendran
JournalCritical care medicine (Crit Care Med) Vol. 42 Issue 10 Pg. e642-53 (Oct 2014) ISSN: 1530-0293 [Electronic] United States
PMID25014067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Anti-Inflammatory Agents
  • Cytokines
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Acriflavine
  • Doxycycline
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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: