Mesenchymal Stromal Cells Alleviates Experimental Acute Respiratory Distress Syndrome through the Cholinergic Anti-Inflammatory Pathway

Abstract

Background & Aim Acute respiratory distress syndrome (ARDS) is a severe hypoxemic respiratory failure characterized by recognizable diffuse alveolar damage and lung injury, with high mortality. Unfortunately, the current treatment for ARDS is mainly supportive. Although preclinical models of ARDS have demonstrated that mesenchymal stromal cells (MSCs) protects the lung against injury, their mechanisms are not yet fully understood. Accumulating evidence has indicated that the cholinergic anti-inflammatory pathway (CAP) is involved in controlling inflammation in various inflammatory situations, we then investigate whether CAP play the critical role in the therapeutic effect of MSC to mitigate ARDS. Methods, Results & Conclusion Lipopolysaccharide (LPS)-induced lung injury model was induced in C57BL/6J mice by nasal drip, followed by an intravenous injection of MSCs or saline 6 hours later. Lung tissue was profiled in three groups of MSC or saline treatment in lung-injury mice and sham in wild type mice. AR-R1779HCl and Methyllycaconitine citrate were used to specifically activate or block α7nAChR respectively. Indomethacin and MF63, inhibiting PTGES and PGES-1 respectively, were used to restrain MSC producing PGE2. After MSC infusions to LPS-induce lung injury mice, the pulmonary vascular permeability were improved and inflammatory cell infiltration were reduced within 6 hours. The expression profile sequencing of lung tissue showed that ChAT, VAChT and other cholinergic system-related genes were significantly increased after MSC treatment. When specifically blocking the acetylcholine (ACh) receptor 7nAChR, the therapeutic effects of MSC significantly reduced, suggesting that the cholinergic anti-inflammatory pathway (CAP) may play an important role in MSC treating ARDS. Moreover, prostaglandin E2 (PGE2) produced by MSC, likely to increase ChAT synthesis of cholinergic nerves. These results supported that MSCs inhibit severe inflammatory response of ARDS through activating CAP-mediated anti-inflammatory regulation, partially through increasing the synthesis of acetylcholine via PGE2. In summary, we have revealed a previously unrecognized mechanism of MSC-mediated activation of the cholinergic anti-inflammatory pathway in alleviating ARDS-like syndrome, which provide evidences for clinical translation of MSC in patients with ARDS.