Overcoming ischemia-reperfusion injury (I/R) is a critical event leading to successful therapeutic lung transplantation. Our research proposal will test the overall hypothesis that Th1-CD4+ T-lymphocytes promote granulocytic-mediated microvascular permeability increase in the post-ischemic lung in part by CD4O-CD4OL binding and chemokine generation. The hypothesis will be tested through experimentation designed to address the following three specific aims: I) Interference with CD4O-CD4OL interaction attenuates I/R-induced microvasculai injury; II) Interleukin-10 (IL-10), which inhibits Th1 -CD4+ lymphocyte-dependent inflammatoryresponses, prevents I/R-induced lung injury via modulation of Th1 -CD4+ lymphocyte adhesion and activation and chemokine production; and III) Th1-CD4+ lymphocyte/ endothelial cell interactions in the post-alveolar microcirculation result in I/R induced permeability changes to this vascular segment. We will measure circulating lymphocyte numbers and differentiate lymphocyte subsets using flow cytometry in isolated rat and mouse lungs that are subjected to defined periods of I/R. We will also determine microvascular damage due to I/R in isolated rat and mouse lungs by measuring the microvascular filtration coefficient (Kfc). Changes in Kf about will then be used to determine the contribution of CD4O-CD4OL signaling in the I/R injury process using antibodies specific to each of these molecule' and through the use of genetically engineered mice. The protective effects of IL- 10 against I/R-induced lung damage will be tested in a similar manner. Assessment of chemokine production, specifically MIP-2 in the rat and mouse lung, will be performed in all experiments. Finally, we will determine whether the I/R-induced increase in Kfc within the post-alveolar microcirculation is due to lymphocytic-mediated inflammatory processes, using segmental permeability measures and by employing immunohistochemistry techniques for identifying the localization of CD4O in formalin-fixed tissues. The results of these studies will provide novel insight as to the role of lymphocytes in acute I/R-induced lung damage with the overall goal of improving success rates for clinical lung transplantation procedures.
| Townsley, Mary I (2012) Structure and composition of pulmonary arteries, capillaries, and veins. Compr Physiol 2:675-709 |
| Townsley, Mary I; Morisseau, Christophe; Hammock, Bruce et al. (2010) Impact of epoxyeicosatrienoic acids in lung ischemia-reperfusion injury. Microcirculation 17:137-46 |
