Abstract
BackgroundSepsis is a severe medical condition that ranks among the top 10 causes of death worldwide and which has permanently high incidence rates. Mesenchymal stem cells (MSCs) have been found to be potent modulators of immune responses. More importantly, there is evidence that MSCs have a beneficial effect on preclinical models of polymicrobial sepsis. However, the changes caused by the MSCs in the effector cells of the host immune system remain unclear.MethodsA mouse model of sepsis (male C57BL/6 mice) with three experimental groups was used for experiments in vivo: a control group, an untreated septic group, and a septic group treated with MSCs. In vitro experiments were performed using a cell line of pulmonary macrophages (RAW 264.7) co-cultured with MSCs and stimulated with lipopolysaccharide (LPS).ResultsIn vivo we demonstrated that treatment with MSCs was able to reduce the expression of cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB), and thereby decrease the production of inflammatory cytokines. In vitro experiments using a co-culture of macrophages with MSCs showed a decrease in COX-2 and NF-κB, and showed that this reduction was directly related to the ability of MSCs to inhibit phosphorylation of ERK, RSK, and p38, enzymes that belong to the family of mitogen-activated protein kinases (MAPKs).ConclusionsThis study demonstrated that MSCs are able to inhibit the MAPK pathway activation, modulating the inflammatory response during sepsis. This understanding that MSCs can remodel the response of host cells and improve the course of sepsis is essential for developing new treatments for this pathology.
Highlights
Sepsis is a severe medical condition that ranks among the top 10 causes of death worldwide and which has permanently high incidence rates
mesenchymal stem cell (MSC) administration ameliorates inflammation on sepsis in the lung As a first step, we used two models of sepsis induction in mice to verify the ability of MSCs to decrease pulmonary inflammation
Our study suggests that MSC injection into a sepsis model can improve the inflammation acting via inhibition of the Mitogen-activated protein kinase (MAPK) pathway by generating decreased production of inflammatory mediators
Summary
Sepsis is a severe medical condition that ranks among the top 10 causes of death worldwide and which has permanently high incidence rates. Even with appropriate antibiotic and resuscitative therapies, sepsis carries a 30% mortality rate and significant morbidity associated with organ failure [2]. It incurs a staggering $16.7 billion cost in the US health economy, with over 750,000 annual cases and greater than 200,000 deaths each year [3]. The role of the immune response is crucial to fight infection; it is responsible for the inflammatory tissue infiltration and severe organ damage, both hallmarks of sepsis [5]. Evidence suggests that modulation of pro- and anti-inflammatory factors contributes to the suppression of immune effector cells, induces the systemic inflammation, and causes tissue damage during the sepsis [6]
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