CD38 Inhibition Results in Sustained Lung Function Following Ischemia Reperfusion Injury

D. A.. Gouchoe¹, Y. Lee¹, J. Kim¹, S. M. Black¹, B. A. Whitson^2
1COPPER Lab, The Ohio State University Wexner Medical Center, Columbus, Ohio ²The Ohio State University Wexner Medical Center, Columbus, Ohio

Purpose: Ischemia reperfusion injury (IRI) has deleterious effects on allograft integrity following lung transplantation. A common pathway leading to injury revolves around Cluster of Differentiation 38 (CD38), and inhibition would offer cellular protection. In this study, we aimed to quantify a therapeutic benefit of CD38 inhibition in transplant relevant IRI.

Methods: C57BL/6J wild-type (WT) or CD38 knock-out (CD38ko) mice were randomly assigned to either: sham injury or IRI (n=6/group). Additionally, WT mice were subjected to sham or IRI with the addition of 78C (n=6/group), the most well-known CD38 inhibitor. Mice were then subjected to 1-hour of ischemia (via left lung hilar clamp), followed by 24-hours of reperfusion. Prior to sacrifice, mice were subjected to invasive lung physiologic and mechanic testing. Tissue, BAL and blood samples were collected at sacrifice and used to quantify the extent of lung injury via histology and biochemical assays. Comparative statistics were used to compare each group.

Results: Following 1-hour of ischemic injury, and subsequent 24-hours of reperfusion, mice in the CD38ko IRI group had the highest inspiratory capacity (IC), and when compared to WT IRI had significantly higher IC (Figure 1A). The CD38ko IRI group also had significantly higher static compliance (Cst) when compared to WT IRI group alone (Figure 1B). Elastance (Ers) was significantly decreased in the CD38ko sham and IRI group as compared to WT IRI. Area, which serves as a surrogate for hysteresis (i.e. measure of alveolar de-recruitment), was significantly increased in the CD38ko IRI group as well (Figure 1C). In all measurements of lung function, genetic ablation of CD38 resulted in a trend towards improved lung function as compared to the baseline WT sham animals. With the addition of 78C, WT sham had significantly higher IC when compared to WT IRI alone (Figure 1D). There was a trend of the WT IRI + 78C group to have higher Cst (Figure 1E) and lower Ers when compared to WT IRI alone, however not significant. Finally, the WT IRI + 78C had significantly higher Area when compared to WT IRI (Figure 1F).

Conclusion: The genetic ablation of CD38 resulted in significantly increased lung function following IRI as compared to WT mice. CD38 inhibition, through pharmacologic means by 78C resulted in a similar improvement. CD38 inhibition may offer a novel approach to protect lung allografts following IRI in a transplantation setting, and ultimately preserve lung function at levels similar to lungs without ischemic injury. Evaluation of optimal delivery of CD38 inhibitors is warranted with findings needing to be further substantiated in pre-clinical models of lung transplantation.

Identify the source of the funding for this research project: BAW is supported through the National Institutes of Health National Heart Lung and Blood Institute grant R01HL143000. SMB is supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK1234750. This research was also generously supported through the Jewel and Frank Benson Family Endowment and The Jewel and Frank Benson Research Professorship at The Ohio State University.