Mesenchymal stem cells enhance survival and bacterial clearance in murineEscherichia colipneumonia

Abstract

Rationale Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied. Objective This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia. Methods and results Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli. 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p<0.05 for MSC vs 3T3 and PBS groups) and lung injury compared with control mice. In addition, wild-type MSCs enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups. The antibacterial effect with MSCs was due, in part, to their upregulation of the antibacterial protein lipocalin 2. Conclusions Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs.

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…37,38,[48][49][50][51] This antibacterial eff ect is partly mediated by improved phagocytic activity of host immune cells such as macrophages, 38,41 monocytes, 48 neutrophils, 49 and ITGAMpositive cells (monocytes, macrophages, and neutrophils). 38 Studies using ex-vivo human lungs have reported similar fi ndings.…”

“…In vitro, mouse MSCs have been reported to increase the production of the antimicrobial peptide lipocalin-2 51 and human MSCs produce LL-37 50 in response to infectious and infl ammatory stimuli. Use of a blocking antibody for both of these peptides nullifi ed the antimicrobial eff ects of MSCs in vivo.…”

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

“…Data from murine colitis models have shown that human adipose-derived MSCs protect against dextran-induced colitis by decreasing the secretion of proinflammatory cytokines and chemokines (6). However, the antimicrobial effector molecules in vertebrate MSCs are not universally the same (4)(5)(6)(7)(8)(9)(10)(11). The antimicrobial effect of unstimulated hMSCs is mediated by the cathelicidin, LL-37 (4), as shown both in vitro and in vivo.…”

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

“…Pathophysiologic mechanisms of ALI and ARDS include inflammation and increased endothelial and epithelial permeability to protein, resulting in extravascular accumulation of protein-rich edema fluid and alveolar epithelial injury (1). Several preclinical studies have demonstrated that bone marrow-derived mesenchymal stem (stromal) cells (MSCs) reduce the severity of ALI induced by endotoxin (2,3), live Escherichia coli bacteria (4,5), or following sepsis (6)(7)(8). Much of the therapeutic benefit of MSCs appears to derive from the release of paracrine soluble factors, which stabilize the injured alveolar epithelium and lung endothelium, reduce inflammation, increase the absorption of pulmonary edema fluid, and have antimicrobial activity (9).…”