Syndecan-2–positive, Bone Marrow–derived Human Mesenchymal Stromal Cells Attenuate Bacterial-induced Acute Lung Injury and Enhance Resolution of Ventilator-induced Lung Injury in Rats

Abstract

What We Already Know about This Topic What This Article Tells Us That Is New Background Human mesenchymal stromal cells demonstrate promise for acute respiratory distress syndrome, but current studies use highly heterogenous cell populations. We hypothesized that a syndecan 2 (CD362)–expressing human mesenchymal stromal cell subpopulation would attenuate Escherichia coli–induced lung injury and enhance resolution after ventilator-induced lung injury. Methods In vitro studies determined whether CD362+ human mesenchymal stromal cells could modulate pulmonary epithelial inflammation, wound healing, and macrophage phagocytosis. Two in vivo rodent studies determined whether CD362+ human mesenchymal stromal cells attenuated Escherichia coli–induced lung injury (n = 10/group) and enhanced resolution of ventilation-induced injury (n = 10/group). Results CD362+ human mesenchymal stromal cells attenuated cytokine-induced epithelial nuclear factor kappa B activation, increased epithelial wound closure, and increased macrophage phagocytosis in vitro. CD362+ human mesenchymal stromal cells attenuated Escherichia coli–induced injury in rodents, improving arterial oxygenation (mean ± SD, 83 ± 9 vs. 60 ± 8 mmHg, P < 0.05), improving lung compliance (mean ± SD: 0.66 ± 0.08 vs. 0.53 ± 0.09 ml · cm H2O−1, P < 0.05), reducing bacterial load (median [interquartile range], 1,895 [100–3,300] vs. 8,195 [4,260–8,690] colony-forming units, P < 0.05), and decreasing structural injury compared with vehicle. CD362+ human mesenchymal stromal cells were more effective than CD362− human mesenchymal stromal cells and comparable to heterogenous human mesenchymal stromal cells. CD362+ human mesenchymal stromal cells enhanced resolution after ventilator-induced lung injury in rodents, restoring arterial oxygenation (mean ± SD: 113 ± 11 vs. 89 ± 11 mmHg, P < 0.05) and lung static compliance (mean ± SD: 0.74 ± 0.07 vs. 0.45 ± 0.07 ml · cm H2O−1, P < 0.05), resolving lung inflammation, and restoring histologic structure compared with vehicle. CD362+ human mesenchymal stromal cells efficacy was at least comparable to heterogenous human mesenchymal stromal cells. Conclusions A CD362+ human mesenchymal stromal cell population decreased Escherichia coli–induced pneumonia severity and enhanced recovery after ventilator-induced lung injury.

Overexpression of IL-10 Enhances the Efficacy of Human Umbilical-Cord-Derived Mesenchymal Stromal Cells in E. coli Pneumosepsis

“…MSCs demonstrate substantial therapeutic promise in preclinical models of pneumonia, ARDS, and sepsis [3,4,5,6,24,25,26,27]. The key relevant mechanisms of action of MSCs include decreased alveolar–capillary barrier permeability [6], enhanced alveolar fluid clearance [28], mitochondrial transfer [27,29], and enhancement of injury resolution and tissue repair [7,8,30].…”

“…The potential for MSCs to favorably modulate the immune response to bacterial infection and tissue injury is a key focus. MSCs have been demonstrated to enhance macrophage function [24] in response to infection, resulting in greater bacterial phagocytosis and killing [3,6,25], reducing tissue bacterial loads, and facilitating injury resolution and tissue repair [4,5]. An important area of investigation is the potential to enhance the immunomodulatory effects of MSCs to further increase their therapeutic potential.…”

“…Second, we studied a single dose and administration route of IL-10 overexpressing MSCs. The dosage regimen was based on prior studies from our group demonstrating that this was an effective regimen in E. coli lung injury [6,25]. We utilized the intravenous route of administration due to prior studies from our group and others demonstrating that this route is as at least as effective as other, more invasive routes such as intrapulmonary or intraperitoneal administration [5,8].…”

Up‐regulation of syndecan‐2 in proximal colon correlates with acute inflammation

“…Syndecan-2 also acts as a receptor for IL-8 and TGF-b (23,24). Recently, syndecan-2 expressed by mesenchymal stromal cells was shown to induce cytokine expression in the lung epithelium and enhance the phagocytic activity of macrophages (25). However, relatively few studies have examined the functions of syndecan-2 during colonic inflammation.…”

Purified β‐glucans from the Shiitake mushroom ameliorates antibiotic‐resistant Klebsiella pneumoniae ‐induced pulmonary sepsis

“…2015; Masterson et al . 2018). The use of rats allows for adequate sample sizes of arterial blood, bronchoalveolar lavage (BAL) fluid and tissues for analysis.…”