title: Activation of hypoxia-inducible factor-1α in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Activation of hypoxia-inducible factor-1α in type 2 cell is a major driver of acute inflammation following lung contusion.
authors.affiliation: 1Department of Surgery, University of Michigan Medical School, Ann Arbor, MI. 2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI. 3Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Madathilparambil V
authors.initials: MV
authors.lastname: Suresh
authors.forename: Sadeesh Kumar
authors.initials: SK
authors.lastname: Ramakrishnan
authors.forename: Bivin
authors.initials: B
authors.lastname: Thomas
authors.forename: David
authors.initials: D
authors.lastname: Machado-Aranda
authors.forename: Yu
authors.initials: Y
authors.lastname: Bi
authors.forename: Nicholas
authors.initials: N
authors.lastname: Talarico
authors.forename: Erik
authors.initials: E
authors.lastname: Anderson
authors.forename: Shah M
authors.initials: SM
authors.lastname: Yatrik
authors.forename: Krishnan
authors.initials: K
authors.lastname: Raghavendran
mesh_terms: D000167:Acriflavine / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003288:Contusions / Q000150:complications / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000502:physiology*; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D055370:Lung Injury / Q000150:complications / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000167:Acriflavine; D004318:Doxycycline