Joanne Lomas-Neira, PhD is an Assistant Professor of Surgery in the Department of Surgical Research at Rhode Island Hospital and a Junior Investigator funded through the CardioPulmonary Vascular Biology COBRE.
Dr. Lomas-Neira is a graduate of the University of Rhode Island receiving undergraduate degrees in Business and Microbiology, a Masters degree in Cytopathology and PhD in Cell/Molecular Biology. Dr. Lomas-Neira did her post-doctoral work in the lab of Dr. Alfred Ayala at Rhode Island Hospital and received her Assistant Professor faculty appointment from Alpert School of Medicine at Brown University in 2013.
Dr. Lomas-Neira received The Rhode Island Foundation award and a Surgical Infection Society Junior Faculty Fellowship. She has 11 first author and 20 co-authored publications. Her work focuses on the roles of angiopoietins 1 and 2 in endothelial and neutrophil activation in the development of Acute Lung Injury. Dr. Lomas-Neira is currently preparing an Ro1 application for independent funding.
Effects of Angiopoietins on shock/sepsis- induced acute lung injury
Acute Lung Injury (ALI) is a complication of trauma characterized by increased microvascular permeability, edema, inflammation, and neutrophil accumulation in the lung. Despite advances in supportive care, trauma patients who develop ALI, still face the risk of significant mortality. While neutrophils have been implicated as playing an important role in the pathogenesis of ALI, vascular endothelial cells (ECs), through their exposure/responsiveness to mediators present in the systemic environment, are also critical to the development of ALI. Using a murine model of hemorrhage (shock) in combination with a subsequent septic challenge, our laboratory has shown that neutrophil interactions with resident pulmonary cells are central to the development of trauma-induced ALI. EC activation, as in vessel remodeling and adhesion and migration of inflammatory cells, is an adaptive response, regulating vascular homeostasis and host defense, respectively. However, the loss of EC barrier function in ALI results in accumulation of fluid, proteins and inflammatory cells within the lung and in compromised gas exchange. This transition from adaptive activation to maladaptive/dysfunction occurs in association with unresolved inflammation. Under normal physiological conditions, regulated expression of two EC effector proteins, Angiopoietins (Ang)-1 & 2 mediates blood vessel formation, remodeling and EC interaction with inflammatory cells. Ang-1 & 2 bind to a tyrosine kinase receptor, Tie2, expressed on endothelial cells (EC). Ang-1 is produced by pericytes, smooth muscle cells, and fibroblasts and is found on the extracellular matrix. Ang-1/Tie2 binding promotes vessel integrity and downstream pro-survival and anti-inflammatory signaling. Ang-2 is stored preformed in EC Weibel-Palade bodies (storage vesicles) and is rapidly released upon EC activation. Unlike Ang-1, binding of Ang-2 plays a role in vascular remodeling and increased vessel permeability. The development of mice over-expressing or deficient in either Ang-1 or 2 has enabled a closer examination of the relationship between these two proteins and their regulation of EC function. Additionaly, it has been proposed that the relative expression of Ang-1 to Ang-2 determines EC responsiveness. In patients that develop ALI plasma Ang-2 levels are significantly elevated. Our recent findings show that Ang-2 is similarly elevated in lung tissue and plasma from mice following shock, in combination with a subsequent septic challenge. Importantly, neutropenic mice do not exhibit this increase. In addition, we have demonstrated that Ang-1:Ang-2 is significantly decreased in mouse lung tissue following shock/sepsis. This decreased ratio is also evident in bronchoalveolar lavage fluid from surgical and trauma ICU patients with ALI suggesting that the altered expression of these two proteins is either predictive or diagnostic of lung injury. However, the actual role Ang-2 plays in shock-induced priming for ALI and regulation of Ang-2’s release/expression has not been examined. To address this, the following central hypothesis is presented:
Angiopoietin-2 promotes loss of pulmonary endothelial barrier function in ALI resulting from the sequential insults of hemorrhagic shock and sepsis and this dysfunction is initiated by EC interaction with activated (shock primed) neutrophils.
Three aims are proposed to test this hypothesis. In Aim 1 we will determine the kinetics of change of Ang-1:Ang-2 in lung tissue and plasma following hemorrhagic shock and/or subsequent septic challenge and assess the role of Ang-1:Ang-2 in the development of ALI and mortality associated with multiple organ failure. This data will be used in Aim 2 to target Ang-1:Ang-2 at selected time points to determine the mechanisms by which Ang-2 changes receptor/adhesion molecule expression and loss of pulmonary endothelial barrier function in mice. In Aim 3 we will determine the degree to which direct EC/PMN interaction regulates the release of Ang-2 and the effects of changes in Ang-1:Ang-2. The data from the proposed study will begin to describe the mechanisms by which PMN-associated, Ang-2-mediated, EC activation leads to ALI. These results are anticipated to provide novel insights into the relationship between the role of angiopoietins in regulating vascular angiogenesis and PMN/EC interactions in the pathogenesis of ALI.
Lomas-Neira J*, Venet F, Chung CS, Thakkar R, Heffernan D, Ayala A — Neutrophil-endothelial interactions mediate angiopoietin-2-associated pulmonary endothelial cell dysfunction in indirect acute lung injury in mice. Am J Respir Cell Mol Biol. 2014 Jan; 50(1):193-200. PMID: 23980650 [PubMed – in process]
Jonathan Reichner, PhD
Department of Surgery
Rhode Island Hospital
Alfred Ayala, PhD
Professor of Surgery
Rhode Island Hospital / the Alpert School of Medicine at Brown University
Ocean State Research Institute
Providence VA Medical Center
830 Chalkstone Avenue
Providence RI 02908
Research Funded by
Research reported in this website was supported by the National Institute of General Medical Science of the National Institutes of Health under grant number P20GM103652.