Although angiogenesis in asthmatic airways has been described decades ago, whether or not the angiogenic milieu contributes to the inflammation is still unknown. Paracrine-acting bone marrow-derived proangiogenic progenitor cells are an integral part of angiogenesis. We are the first to report that proangiogenic progenitors are increased in the peripheral blood circulation in asthma and home into the lungs within hours after allergen challenge, prior to the arrival of inflammatory cells. We are also the first to demonstrate that proangiogenic progenitors in asthma have up-regulated eotaxin expression and secrete this chemokine specifically upon interaction with allergen challenged lung vascular cells. Our preliminary data show that IL-25, primary Th2 cytokine, induced proangiogenic progenitor-derived eotaxin mediates both angiogenesis and inflammation. Based on our data we hypothesize that angiogenesis and inflammation in asthma are initiated by proangiogenic progenitors via IL-25 induced eotaxin expression. In aim 1 we define the role of proangiogenic progenitor-derived eotaxin in angiogenesis and inflammation. The roles of proangiogenic progenitor-derived eotaxin in angiogenesis and inflammation will be revealed by utilization of eotaxin knockout mice for bone marrow transplantation and adoptive transfer of proangiogenic progenitors. Quantification of eotaxin expressed by proangiogenic progenitors isolated from patients will demonstrate any association to airway inflammation and disease severity. In aim 2 we identify mechanisms of eotaxin expression by proangiogenic progenitors. Analysis of eotaxin expression by proangiogenic progenitors during Th1 or Th2 reactions will prove any roles for a Th2 specific response. In vitro stimulation of proangiogenic progenitors with prime Th2-cytokine IL-25, will show its role in the induction of eotaxin expression. Bone marrow transplantation and adoptive transfer with proangiogenic progenitors from IL-25 receptor (IL-17RB) knockout mice will reveal the significance of IL-25 in proangiogenic progenitor-derived eotaxin in angiogenesis and inflammation. Overall the project will provide mechanistic insight into how angiogenesis and inflammation in asthma are linked together. The findings will add a novel mechanism to proangiogenic progenitor induced vascularization. It will help us understand progenitor cell biology in inflammatory lung disease and will impact other angiogenic and inflammatory disorders.
|Program type||Scientist Development Grant|
|Effective start/end date||01/01/2011 → 12/31/2014|