Stem Cell Therapy Effect on the Inflammatory Response in a Porcine Model of Acute Lung Injury

Background Use of mesenchymal stem cells (MSC) in tissue healing has gained considerable interest, especially in complex tissue injuries such as acute lung injury (ALI). The utility of MSCs is currently being evaluated in clinical trials for different diseases, but the mechanism by which treatment may affect pulmonary function in ALI is unclear. Objective We tested the hypothesis that in severe traumatic lung injury resulting in pulmonary hemorrhage and endothelial damage, the inflammatory response at the cellular level may be acutely improved with MSC treatment compared to standard clinical management with ventilator adjustments alone. Design/Methods Perinatal swine (8.5 ± 0.2 kg body weight, n=11) were anesthetized, mechanically ventilated, and catheterized with a pulmonary artery catheter. After obtaining baseline hemodynamic measurements and blood gases to assess pulmonary function and bronchoalveolar lavage (BAL) specimens to examine indices of pulmonary inflammation, oleic acid (0.1 ml/kg) was injected into the pulmonary artery to achieve hemorrhagic ALI. ALI resulted in a decrease (p<0.01) in the PaO2/FiO2 ratio from 489 ± 15 to 227 ± 29 and a doubling (p<0.01) of the pulmonary to systemic vascular resistance ratio (PVR/SVR) from 0.19 ± 0.02 to 0.36 ± 0.03. Piglets were then divided into a group managed by adjusting mechanical ventilation alone (n=5), and a group that was administered MSC (2.0×10 6 cells, n=6) into the pulmonary artery. Pigs were monitored for 10 hours after injury. Post‐experiment, lung specimens were obtained for histological evaluation. Results The PVR/SVR ratio remained elevated in the non‐treated group whereas treatment of ALI with MSC resulted in a decrease in PVR/SVR to 0.26 ± 0.07 two hours after treatment. This vasorelaxation of the pulmonary vasculature with MSC treatment was transient and PVR/SVR returned to elevated levels 4 to 8 hours post‐injury. Oleic acid caused severe vascular endothelial damage resulting in an infiltration of neutrophils in BAL specimens after lung injury (21.1 ± 1.9% proportion of neutrophils per BAL cell count at baseline versus 75.8 ± 3.2% after ALI). This elevation in neutrophils remained in both MSC and non‐treated groups for 10 hours after injury. The proportion of macrophages in BAL samples was similar in both groups and not statistically different from early injury to 8 hours post‐treatment. Cytokine indices of inflammation were examined by measuring changes in TNF‐α, IL‐6, and IL‐10 in BAL specimens. Of these, enhanced stimulation of TNF‐α was noted during the period following MSC treatment ((3.3 ± 1.3 to 58.0 ± 10.2 pg/ml from baseline to injury vs 347 ± 124 pg/ml 8 hours after MSC) whereas non‐treated animals did not show this increase. Conclusions The reduction in PVR/SVR ratio following stem cell treatment of severe ALI endothelial damage may reflect a reduction in pulmonary vasoconstriction due to MSCs creating a temporary barrier to vascular endothelial leakage, thus reducing pulmonary hemorrhage. An effect of MSCs in reducing the inflammatory response to ALI was not evident in this acute period following injury. Rather, enhanced stimulation of TNF‐α 8 hours post MSC treatment may indicate a signaling mechanism for up regulation of a cellular response to enable tissue repair. Further study is needed to determine if MSCs may exert a different effect on restoration of the integrity of the pulmonary capillary‐alveolar air‐liquid barrier if delivered into the alveoli directly versus intravascularly. Support or Funding Information The views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Department of the Army, the Department of Defense, or the U.S. government.