Lung contusion is a common injury sustained by victims of motor vehicular accidents and blast trauma. It is also an independent risk factor for the development of ALI, ARDS and ventilator associated pneumonia. It is frequently associated clinically with gastric aspiration at the time of trauma that can further increase the severity of lung injury and the risk of ALI/ARDS based on our preliminary studies in animals. The current proposal studies murine models of both isolated lung contusion and lung contusion with gastric aspiration. Emphasis is on mechanistic understanding of the protective roles of MCP-1and MCP-5 in the pathogenesis of these injuries alone and in combination, including specific effects of this chemokine in facilitating the recruitment and activation of alveolar macrophages and the subsequent phagocytosis of apoptotic neutrophils. The grant has three Specific Aims.
Aim 1 investigates lung injury and innate pulmonary inflammation in lung contusion in knockout mice lacking MCP-1, MCP-5 or the receptor protein CCR2, as well as in wild type mice given antibodies against these molecules. These in vivo studies are complemented by added experiments where isolated alveolar macrophages are examined ex vivo for phenotypic parameters, phagocytic potential, and cell-specific inflammatory mediator profile. Additionally, an investigation of origin of cells primarily responsible for the production of MCP-1 in lung contusion through the use of bone marrow-derived chimeras is proposed. In addition, the importance of TLR9 with the intracellular adaptor protein MyD 88 as an intermediate in the recognition of injury and the subsequent activation and elaboration of MCP-1 from alveolar macrophages is investigated.
Aim 2 involves analogous studies to those in Aim 1 to define the detailed activities and mechanisms of action of MCP-1 and MCP-5 in the combined injury model of lung contusion with gastric aspiration. The precise mechanisms of activity of chemokines with alveolar macrophage activity and role of TLR9 in the production of MCP-1 or MCP-5 are similar to aim 1.
Aim 3 examines the effects of delivering exogenous MCP-1 to the lungs via direct instillation and by electroporation-facilitated gene delivery of DNA plasmids containing MCP-1 to MCP-1 (-/-) and wild type mice following lung contusion and lung contusion with gastric aspiration. These latter studies extend Aim 1 and 2 to further document the functional significance of MCP-1 in lung contusion with and without gastric aspiration, while at the same time investigating the efficacy of potential future therapies based on the pulmonary delivery of this chemokine or related agents.

Public Health Relevance

This grant seeks to improve understanding about mechanisms contributing to lung contusion and gastric aspiration, two important human pulmonary diseases (lung injuries) that frequently occur in conjunction with blunt chest trauma. Research in the proposal studies the behavior of specific substances in the pulmonary inflammatory response in these diseases, particularly the chemokines MCP-1 and MCP-5 that affect the activity and recruitment of important inflammatory cells such as macrophages. The grant not only studies mechanisms by which early increases in MCP-1 and MCP-5 may aid the timely resolution of acute inflammatory injury during lung contusion with or without gastric aspiration, but also investigates the effects of related pharmacologic and gene delivery approaches to lay the groundwork for possible future chemokine- based drug or gene therapies for these important lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102013-04
Application #
8423743
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Harabin, Andrea L
Project Start
2010-04-01
Project End
2014-02-28
Budget Start
2013-04-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$364,033
Indirect Cost
$128,413
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Dolgachev, V A; Goldberg, R; Suresh, M V et al. (2016) Electroporation-mediated delivery of the FER gene in the resolution of trauma-related fatal pneumonia. Gene Ther 23:785-796
Suresh, Madathilparambil V; Thomas, Bivin; Dolgachev, Vladislav A et al. (2016) Toll-Like Receptor-9 (TLR9) is Requisite for Acute Inflammatory Response and Injury Following Lung Contusion. Shock 46:412-9
Suresh, Madathilparambil V; Thomas, Bivin; Machado-Aranda, David et al. (2016) Double-Stranded RNA Interacts With Toll-Like Receptor 3 in Driving the Acute Inflammatory Response Following Lung Contusion. Crit Care Med 44:e1054-e1066
Ramakrishnan, Sadeesh K; Taylor, Matthew; Qu, Aijuan et al. (2014) Loss of von Hippel-Lindau protein (VHL) increases systemic cholesterol levels through targeting hypoxia-inducible factor 2α and regulation of bile acid homeostasis. Mol Cell Biol 34:1208-20
Machado-Aranda, David; V Suresh, Madathilparambil; Yu, Bi et al. (2014) Alveolar macrophage depletion increases the severity of acute inflammation following nonlethal unilateral lung contusion in mice. J Trauma Acute Care Surg 76:982-90
Suresh, Madathilparambil V; Ramakrishnan, Sadeesh Kumar; Thomas, Bivin et al. (2014) Activation of hypoxia-inducible factor-1α in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion. Crit Care Med 42:e642-53
Dolgachev, Vladislav A; Yu, Bi; Sun, Lei et al. (2014) Interleukin 10 overexpression alters survival in the setting of gram-negative pneumonia following lung contusion. Shock 41:301-10
Machado-Aranda, David; Raghavendran, Krishnan (2014) Electroporation-mediated delivery of genes in rodent models of lung contusion. Methods Mol Biol 1121:205-21
Miller, Douglas L; Suresh, M V; Dou, Chunyan et al. (2014) Characterization of ultrasound-induced pulmonary capillary hemorrhage in rats. Microvasc Res 93:42-5
Machado-Aranda, David; Wang, Zhengdong; Yu, Bi et al. (2013) Increased phospholipase A2 and lyso-phosphatidylcholine levels are associated with surfactant dysfunction in lung contusion injury in mice. Surgery 153:25-35

Showing the most recent 10 out of 20 publications