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All‐trans retinoic acid (ATRA) or mesenchymal stem cells (MSCs) have been shown to promote lung tissue regeneration in animal models of emphysema. However, the reparative effects of the combination of the two and the role of p70S6 kinase‐1 (p70S6k1) activation in the repair process have not been defined. Twenty‐one days after intratracheal instillation of porcine pancreatic elastase (PPE), MSC and/or 10 days of ATRA treatment was initiated. Thirty‐two days later, static lung compliance (Cst), mean linear intercepts (MLIs), and alveolar surface area (S) were measured. After PPE, mice demonstrated increased values of Cst and MLI, and decreased Svalues. Both ATRA and MSC transfer were individually effective in improving these outcomes while the combination of ATRA and MSCs was even more effective. The combination of p70S6k1−/−MSCs transfer followed by ATRA demonstrated only modest effects, and rapamycin treatment of recipients with wild‐type (WT) MSCs and ATRA failed to show any effect. However, transfer of p70S6k1over‐expressing‐MSCs together with ATRA resulted in further improvements over those seen following WT MSCs together with ATRA. ATRA activated p70S6k1 in MSCs in vitro, which was completely inhibited by rapamycin. Tracking of transferred MSCs following ATRA revealed enhanced accumulation and extended survival of MSCs in recipient lungs following PPE but not vehicle instillation. These data suggest that in MSCs, p70S6k1 activation plays a critical role in ATRA‐enhanced lung tissue repair, mediated in part by prolonged survival of transferred MSCs. p70S6k1‐activated MSCs may represent a novel therapeutic approach to reverse the lung damage seen in emphysema. StemCellsTranslationalMedicine2018;7:551–558 In an animal model of emphysema, administration of bone marrow‐derived mesenchymal stem cells (MSCs) followed by all‐trans retinoic acid (ATRA) treatment induced lung tissue repair. In this process, mTOR‐p70S6k1 signaling pathway‐activated by ATRA in MSCs played a critical role, mediated in part by prolonged survival of transferred MSCs.

When wild-type BALB/c mice were transferred with OVA-specific Th2 cells followed by OVA inhalation, a severe eosinophilia, mucus hypersecretion and airway hyper-responsiveness (AHR) was induced in parallel with a marked elevation of IL-4, IL-5 and IL-13 levels in bronchoalveolar lavage fluid (BALF). However, neither eosinophilia, AHR nor mucus hypersecretion was induced in Th2 cell-transferred STAT6−/− mice. The failure of eosinophilia was not due to the defect of Th2 cytokine production in BALF of STAT6−/− mice transferred with Th2 cells, but because of the defect of STAT6-dependent eotaxin production. Indeed, intranasal administration of eotaxin reconstituted pulmonary eosinophilia but not AHR and mucus hypersecretion in OVA-inhalated STAT6−/− mice. These results initially provided direct evidence that STAT6-dependent eotaxin production is essential for pulmonary eosinophilia. We also dissociated the role of STAT6 for eosinophilia from that for AHR and mucus hypersecretion. Thus, STAT6 also plays a critical role at late phase of Th2-dependent allergy induction.

Auranofin, aurothioglucose and aurothiomalate (10 μM each) inhibited 12-O-tetradecanoylphorbol 13-acetate (TPA, 16.2 nM)-induced nuclear translocation of nuclear factor-kappa B (NF-κB), and production of nitric oxide (NO) and prostaglandin E2(PGE2) in rat peritoneal macrophages when the cells were pre-incubated with each gold compound for 20h. Without pre-incubation for 20h, aurothioglucose and aurothiomalate, but not auranofin, failed to inhibit the TPA-induced NF-κB nuclear translocation and production of NO and PGE2. Auranofin, aurothioglucose and aurothiomalate did not affect the direct binding of NF-κB to the DNA probe. It was suggested that these gold compounds inhibit the TPA-induced production of NO and PGE2by inhibiting the NF-κB nuclear translocation.

Auranofin, aurothioglucose and aurothiomalate (10 μM each) inhibited 12‐O‐tetradecanoylphorbol 13‐acetate (TPA, 16.2 nM)‐induced nuclear translocation of nuclear factor‐kappa B (NF‐κB), and production of nitric oxide (NO) and prostaglandin E2(PGE2) in rat peritoneal macrophages when the cells were pre‐incubated with each gold compound for 20h. Without pre‐incubation for 20h, aurothioglucose and aurothiomalate, but not auranofin, failed to inhibit the TPA‐induced NF‐κB nuclear translocation and production of NO and PGE2. Auranofin, aurothioglucose and aurothiomalate did not affect the direct binding of NF‐κB to the DNA probe. It was suggested that these gold compounds inhibit the TPA‐induced production of NO and PGE2by inhibiting the NF‐κB nuclear translocation.