Activation of Hypoxia-Inducible Factor-1 alpha in Type 2 Alveolar Epithelial Cell Is a Major Driver of Acute Inflammation Following Lung Contusion

作者：Suresh Madathilparambil V; Ramakrishnan Sadeesh Kumar; Thomas Bivin; Machado Aranda David; Bi Yu; Talarico Nicholas; Anderson Erik; Yatrik Shah M; Raghavendran Krishnan^*

来源：Critical Care Medicine, 2014, 42(10): E642-E653.

DOI：10.1097/CCM.0000000000000488

• cytokines
• hypoxia-inducible factor-1 alpha
• lung contusion
• oxygen-dependent degradation domain luciferase mice
• type 2 cells

Objective: Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. Hypoxia-inducible factor-1 alpha 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 alpha 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 alpha 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 alpha conditional knockout mice were isolated and evaluated for proinflammatory cytokines following lung contusion. Finally, the role of nuclear factor-kappa B and interleukin-1 beta as intermediates in this interaction was studied.
Results: Lung contusion induced profound global hypoxia rapidly. Increased expression of hypoxia-inducible factor-1 alpha 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 beta, 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-kappa B. Hypoxia-inducible factor-1 alpha in lung epithelial cells was shown to regulate interleukin-1 beta promoter activity.
Conclusion: Activation of hypoxia-inducible factor-1 alpha in type 2 cell is a major driver of acute inflammation following lung contusion.

• 出版日期2014-10