Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

Abstract

Previous studies demonstrated that bone marrow–derived mesenchymal stem (stromal) cells (MSCs) reduce the severity of acute lung injury in animal models and in an ex vivo perfused human lung model. However, the mechanisms by which MSCs reduce lung injury are not well understood. In the present study, we tested the hypothesis that human MSCs promote the resolution of acute lung injury in part through the effects of a specialized proresolving mediator lipoxin A4 (LXA4). Human alveolar epithelial type II cells and MSCs expressed biosynthetic enzymes and receptors for LXA4. Coculture of human MSCs with alveolar epithelial type II cells in the presence of cytomix significantly increased the production of LXA4 by 117%. The adoptive transfer of MSCs after the onset of LPS-induced acute lung injury (ALI) in mice led to improved survival (48 h), and blocking the LXA4 receptor with WRW4, a LXA4 receptor antagonist, significantly reversed the protective effect of MSCs on both survival and the accumulation of pulmonary edema. LXA4 alone improved survival in mice, and it also significantly decreased the production of TNF-α and MIP-2 in bronchoalveolar lavage fluid. In summary, these experiments demonstrated two novel findings: human MSCs promote the resolution of lung injury in mice in part through the proresolving lipid mediator LXA4, and LXA4 itself should be considered as a therapeutic for acute respiratory distress syndrome.

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

“…61, 62), and 15 μM WRW4 (a selective ALX/FPR2 inhibitor; refs. [62][63][64], all dissolved in PBS. Mice were euthanized by CO 2 asphyxiation 18 hours after KA treatment, and the eyes were fixed in 4% paraformaldehyde.…”

Metabolism and phospholipid assembly of polyunsaturated fatty acids in human bone marrow mesenchymal stromal cells

“…Prostaglandin E2 (PGE2; derivative of 20:4n-6) is known to affect the proliferation and cytokine secretion of T cells, and thus has a major role in MSC immunoregulation (21). Recently, lipoxins and resolvins have been identified as essential regulators of the resolution phase of inflammation (22) and as players in the immunoregulation of MSCs (23).…”

Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer

“…Importantly, depletion of AMs abrogated MSCs' protective effects in this model, suggesting that AMs are key cellular mediators of MSCs' effects. Although contact-dependent mechanisms such as these are important, a large body of evidence suggests that MSCs' therapeutic effects are mediated by paracrine factors (20)(21)(22). Recently, EVs have emerged as an important component of the MSC secretory repertoire.…”