β2肾上腺素能受体激动剂通过cAMP/PKA通路调控MSCs旁分泌在急性肺损伤修复中的作用和机制

Mesenchymal stem cells (MSCs) were found to be able to modulate inflammation and help lung injury repair by interacting with inflammatory cells through some paracrine cytokines. Adrenergic receptors might participate in the proliferation, differentiation, mobilization and secretion of MSCs. It remains unclear whether adrenergic receptors could modulation the paracrine effects of MSCs. Our prior studies showed thatβ2 adrenergic receptor agonists could enhance the paracrine effects of MSCs, attenuate inflammation and help lung injury repair, while the exact mechanisms remain unclear. Thus, we proposed this hypothesis:β2 adrenergic agonists could enhance the paracrine effects of MSCs through cAMP/PKA pathway, thus help modulate inflammation repair the injured lung. In order to validate this hyposis, we will discuss the role and mechanism of β2 adrenergic agonists on the paracrine effects of MSCs through cAMP/PKA pathway in acute lung injury by means of ELISA, real time-PCR, Western blot, lentivirus vector transfection and RNA interference in human MSCs, primary cultured macrophages and LPS injured mice models. By focusing on a new viewpoint of modulating MSCs’ paracrine effects byβ2 adrenergic agonists, this project will further reveal the mechanisms of the onset and repair in lung injury, and provide theoretical/experimental support for improving therapeutic effects of MSCs.

间充质干细胞（MSCs）通过旁分泌与炎症细胞相互作用，调节炎症反应，促进肺损伤修复。肾上腺素能受体能否调控MSCs旁分泌仍知之甚少。我们的预实验提示，β2肾上腺素能受体激动剂有促进MSCs旁分泌、下调炎症反应和减轻肺损伤的作用,但具体机制不清楚。为此，我们提出假说：β2肾上腺素能受体可能通过cAMP/PKA信号通路调控MSCs旁分泌、炎症反应和肺损伤修复。为了验证这一假说，我们将通过人骨髓MSCs细胞株、小鼠原代巨噬细胞和LPS肺损伤模型，采用real time-PCR、Western blot、慢病毒转染等手段，从分子、细胞和动物水平等多方面探讨β2受体激动剂调控MSCs旁分泌在肺损伤修复中的作用，明确其通过cAMP/PKA通路调控旁分泌的机制。本研究将从β2受体激动剂调控MSCs旁分泌这个新视点为揭示急性肺损伤的发生和修复机制奠定基础，也为改进MSCs移植疗效提供新的思路。

间充质干细胞（MSCs）通过旁分泌与炎症细胞相互作用，调节炎症反应，促进肺损伤修复。肾上腺素能受体能否调控MSCs旁分泌仍知之甚少。本实验主要采用real time-PCR、Western blot、Transwell等手段，从分子、细胞和动物水平等多方面对β2受体激动剂调控MSCs旁分泌在肺损伤修复中的作用进行了探讨。研究结果发现：沙美特罗刺激MSC后静脉移植可以减轻小鼠LPS肺损伤，这一作用与沙美特罗促进MSC旁分泌IL-1ra有关，其中cAMP/PKA 信号通路对IL-1ra的分泌发挥了重要作用。本研究将从β2受体激动剂调控MSCs旁分泌这个新视点为揭示急性肺损伤的发生和修复机制奠定基础，也为改进MSCs移植疗效提供新的思路。