The Sharma laboratory investigates the molecular mechanisms of lung ischemia-reperfusion injury (IRI), and identifying therapeutic strategies to prevent IRI after lung transplantation. Our studies explore the role of myeloid-derived suppressor cells (MDSCs) and their crosstalk with alveolar macrophages, CD4+ iNKT cells as well as alveolar epithelial cells, in lung IRI.
Therapeutic options include mesenchymal stem cell-derived extracellular vesicles and specialized pro-resolving specialized lipid mediators in the mitigation of lung IRI. Ongoing research projects are summarized here:
- Immunomodulation of lung IRI by myeloid-derived suppressor cells via CXCR2 and CCR2-dependent signaling. Contribution of innate immune cell population of MDSC subsets and their recruitment to the lung after IRI through chemokine receptor CXCR2+ G(granulocytic) -MDSCs and CCR2+ M(monocytic)-MDSCs is being investigated in primary graft dysfunction (PGD) and lung IRI. Our central hypothesis is that M-MDSCs demonstrate an immunosuppressive phenotype via modulation of IL-10/IL-17 axis in Treg-iNKT cell crosstalk to attenuate early post-lung transplant IRI.
- Resolution of lung IRI by specialized pro-resolving mediators mitigates primary graft dysfunction. We are investigating the role of w-3 fatty acid derived SPMs i.e. Resolvins, Maresins, Lipoxins and Protectins in the immunomodulation of macrophage phenotype, enhanced efferocytosis and inhibiting ferroptosis for the attenuation of pul monary inflammation and resolution of primary graft dysfunction.
- Mesenchymal stem cell-derived extracellular vesicles in mitigation of lung ischemia-reperfusion injury and enhancement of donor lung rehabilitation. The focus of this project is to delineate the protective role of mesenchymal stem cells and its derivatives (extracellular vesicles) in the attenuation of lung IR injury via regulation of specific microRNAs. Moreover, supplementation of ex vivo lung perfusion with modified microvesicles is postulated to enhance rehabilitation of DCD (donation after cardiac death) lungs.
- Pannexin-1/TRPV4/eNOS signaling in endothelial permeability regulation during lung transplant injury. The aim of this project is to pinpoint the contributory role of Pannexin-1 ATP release in activating DAMPs and calcium sensitive transient receptor potential vanilloid 4 (TRPV4) channels on the pulmonary endothelium to regulate leukocyte trafficking during lung transplant injury.
The Atkinson laboratory studies innate and adaptive immune mechanisms in solid organ transplantation. The laboratory has focused over recent years on understanding how donor injuries and recipient pre-transplant immunity contribute the development of early graft injury, ischemia reperfusion injury, and both acute and chronic rejection. These mechanistic studies have led to the development of novel rodent models of donor brain death, donation after cardiac death, ex-vivo perfusion, and the development of targeted therapeutics to treat the donor and recipients. Our laboratory uses state of the art in-vitro techniques and immunological assays in concert with rodent and large animal models of lung transplantation to explore the immunological mechanisms that promote graft injury. Ongoing lung transplant projects are summarized:
- Target complement inhibition in lung transplantation: Complement activation plays a key role in the pathogenesis of ischemia reperfusion injury, the extent to which has been shown to be correlated with the development of primary graft dysfunction. Our laboratory has developed a series of novel lung targeted complement inhibitors that inhibit complement at the level of the graft. Our central hypothesis is that lung targeted complement inhibition will modulate pathogenic complement activation in the graft within adversely effecting systemic complement host immune functions.
- Autoimmunity and lung transplantation: Autoimmune mechanisms play a central role in the development and perpetuation of chronic lung disease. While mechanisms that contribute to alloimmunity post-transplantation are well characterized the impact of pre-existing autoimmunity to lung transplant outcomes are incompletely elucidated. We have developed rodent models of lung autoimmunity and paired these with the rodent orthotopic lung transplant model to dissect the impact of autoimmunity of both early and late graft outcomes. We hypothesize that modulation of these autoimmune responses will reduce alloimmunity and improve graft outcomes.
- Cell-cell signaling in endothelial permeability regulation during lung transplant injury. The aim of this project is to better understand the mechanisms by which endothelial cells communicate and signal to promote sustained barrier functions. Our studies are investigating endothelial-endothelial and endothelial-immune cell interactions to learn how this communication promotes injury and immune priming. In pursuit of these mechanistic studies, we utilize state of the art organ on a chip in-vitro assays, ex-vivo lung perfusion, and rodent models to dissect mechanism and develop novel target nanotherapeutics.
- IgG Glycotypes associated with lung transplant primary graft dysfunction. Donor specific antibody functions are controlled by the IgG sub-type and changes to the glycans present on the Fc portion of the antibody. The aim of this study is to determine which IgG glycotypes are associated with primary graft dysfunction and further dissect the mechanisms that lead to antibody modifications that can cause increased antibody effector functions. In collaboration with the Glycopath and the biochemistry department at the University of Florida we have screened and are developing assays to investigate glycan biology on donor specific antibodies. We are using these novel techniques to better understand how glycan alterations effect function and how these changes impact lung transplant outcomes.
Complement driven innate and adaptive autoreactivity in lung transplantation Investigates the role of pre-existing autoimmunity on lung transplant outcomes.
Graft-targeted anti-complement therapy to reduce cardiac graft injury and allograft vasculopathy
Improving marginal allograft outcomes through cell junction stabilization in transplantation
IgG Glycotypes associated with lung transplant primary graft dysfunction
David and Kim Raab Foundation
Protective role of mesenchymal stem cells in lung transplant injury