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Diffuse Lung Disease |

Annexin A2 Modulates Bleomycin-Induced Interstitial Pulmonary Edema FREE TO VIEW

Min Luo, PhD; Huigen Chen, MS; Frances West, MD; Dena Almeida, BS; Stefan Worgall, MD; Katherine Hajjar, MD
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Department of Cell and Developmental Biology, Department of Pediatrics, Weill Cornell Medical College, New York, NY


Chest. 2015;148(4_MeetingAbstracts):390A. doi:10.1378/chest.2279544
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Abstract

SESSION TITLE: Diffuse Lung Disease Poster Discussions

SESSION TYPE: Original Investigation Poster Discussion

PRESENTED ON: Wednesday, October 28, 2015 at 02:45 PM - 04:00 PM

PURPOSE: Interstitial lung disease (ILD) is a broad category of lung disorders characterized by varying degrees of inflammation and fibrosis. Increased procoagulant and decreased fibrinolytic activities are commonly observed in the lungs of ILD patients. However, it is unclear whether fibrinolysis contributes to fibrosis because fibrinogen-deficient mice display similar levels of fibrosis as wildtype mice in response to bleomycin, whereas plasminogen- and tissue plasminogen activator (tPA)-deficient mice show more severe fibrosis in this model. Annexin A2 (A2) regulates the fibrinolytic system by binding plasminogen, tPA, and accelerating the production of plasmin. Here, we report a novel function of A2, whereby it modulates bleomycin-induced lung injury by stabilizing the pulmonary vasculature in a manner independent of its profibrinolytic activity.

METHODS: Anxa2-/- and Anxa2+/+ mice were injected intratracheally with either bleomycin or saline. Two weeks later, lung dynamics were assessed and pulmonary vascular integrity evaluated by measuring extravasation of intravenously-injected Evans blue dye. Collagen deposition in the lung was quantified by hydroxyproline analysis. Hematoxylin and eosin and Masson’s trichrome staining were used to evaluate tissue architecture. Immunostaining was employed to identify infiltrating cells, fibrin deposition, and apoptosis.

RESULTS: In comparison to the Anxa2+/+ lung, Anxa2-/- lung tissue revealed areas of hemorrhage in addition to increased Evans blue extravasation, and robust inflammatory cell infiltration, apoptosis and fibrin deposition. Two weeks later, lungs from bleomycin-treated Anxa2-/- mice displayed lower static compliance and higher elastance compared to wildtype controls. Reducing fibrin deposition through Ancrod treatment did not affect the difference in lung stiffness between bleomycin-treated Anxa2-/- and Anxa2+/+ mice. In addition, there was no significant difference in collagen deposition between bleomycin-treated Anxa2-/- and Anxa2+/+ lungs.

CONCLUSIONS: These data indicate that A2 modulates vascular permeability and the inflammatory response in the bleomycin-injured lung. Depletion of A2 results in severe hemorrhage, increased inflammation, fibrin deposition, and accelerated lung stiffness under bleomycin challenge in a manner that is independent of the fibrinolytic function of A2.

CLINICAL IMPLICATIONS: These data offer novel mechanistic insights into the pathogenesis of bleomycin-induced lung injury.

DISCLOSURE: The following authors have nothing to disclose: Min Luo, Huigen Chen, Frances West, Dena Almeida, Stefan Worgall, Katherine Hajjar

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