S. Chiu1, H. Makinde1, M. Akbarpour1, H. Perlman2, J. I. Sznajder2, G. S. Budinger2, S. J. Schwulst1, A. Bharat1 1Northwestern University,Surgery,Chicago, IL, USA 2Northwestern University,Medicine,Chicago, IL, USA
Introduction: Up to 75% of patients who suffer from traumatic brain injury (TBI) or intracranial hemorrhage develop life-threatening neurogenic pulmonary edema (NPE). Catecholamine surge resulting from TBI has been traditionally postulated to cause pulmonary vasodilation and capillary leak, resulting in NPE. However, cathecholamine antagonists do not confer protection against TBI-associated NPE, suggesting an alternate pathogenesis. Here, we demonstrate that intravascular non-classical monocytes (NCM) play a crucial role in the development of NPE which is ameliorated when NCM are pharmacologically depleted.
Methods: C57BL/6J mice were subject to either sham craniotomy or controlled cortical impact with severe TBI. The neurologic severity score (NSS) was used to evaluate motor and behavioral function following TBI. 24 hours prior to TBI, mice were treated with intravenous clodronate liposomes to deplete pulmonary non-classical monocytes using our recently described protocols. Flow cytometry was used to characterize lung myeloid cell populations at 24 hours after TBI. The ratio of wet- to dry-weight of lungs was used to measure pulmonary edema.
Results: Controlled cortical impact resulted in severe TBI as measured by NSS (Sham: 1.3 vs. TBI: 7.0, p<0.001, Figure A). Controlled cortical impact resulted in NPE, as indicated by a 30% increase in the wet-to-dry ratio of lungs versus controls (Sham: 4.7 vs. TBI: 6.0, **p=0.03, Figure B). NPE was associated with an influx of CD11b+ cells, including NCM and NK Cells (**p=0.03, ***p=0.01, Figure C). Treatment with intravenous clodronate liposomes resulted in selective depletion of intravascular NCM, while preserving interstitial classical monocytes in the lung. Depletion of NCM resulted in protection against NPE (Wet-to-dry ratio 6.0 vs. 4.5, *p<0.001, Figure B), but did not protect against TBI severity (NSS 7.0 vs. 6.5, p=n.s., Figure A). Sham craniotomy and liposome treatment alone did not alter the lung wet-to-dry ratio.
Conclusion: NPE is associated with an influx of non-classical monocytes and NK cells into the lung. Pharmacologic depletion of non-classical monocytes in the lung protected against NPE in this murine model. Ongoing studies will determine whether NCM mediate NPE through the recruitment of NK cells.
