Bone Marrow Derived Mesenchymal Stem Cells Inhibit Inflammation and Preserve Vascular Endothelial Integrity in the Lungs after Hemorrhagic Shock

Abstract

Hemorrhagic shock (HS) and trauma is currently the leading cause of death in young adults worldwide. Morbidity and mortality after HS and trauma is often the result of multi-organ failure such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), conditions with few therapeutic options. Bone marrow derived mesenchymal stem cells (MSCs) are a multipotent stem cell population that has shown therapeutic promise in numerous pre-clinical and clinical models of disease. In this paper, in vitro studies with pulmonary endothelial cells (PECs) reveal that conditioned media (CM) from MSCs and MSC-PEC co-cultures inhibits PEC permeability by preserving adherens junctions (VE-cadherin and β-catenin). Leukocyte adhesion and adhesion molecule expression (VCAM-1 and ICAM-1) are inhibited in PECs treated with CM from MSC-PEC co-cultures. Further support for the modulatory effects of MSCs on pulmonary endothelial function and inflammation is demonstrated in our in vivo studies on HS in the rat. In a rat “fixed volume” model of mild HS, we show that MSCs administered IV potently inhibit systemic levels of inflammatory cytokines and chemokines in the serum of treated animals. In vivo MSCs also inhibit pulmonary endothelial permeability and lung edema with concurrent preservation of the vascular endothelial barrier proteins: VE-cadherin, Claudin-1, and Occludin-1. Leukocyte infiltrates (CD68 and MPO positive cells) are also decreased in lungs with MSC treatment. Taken together, these data suggest that MSCs, acting directly and through soluble factors, are potent stabilizers of the vascular endothelium and inflammation. These data are the first to demonstrate the therapeutic potential of MSCs in HS and have implications for the potential use of MSCs as a cellular therapy in HS-induced lung injury.

CXCR4 Receptor Overexpression in Mesenchymal Stem Cells Facilitates Treatment of Acute Lung Injury in Rats

“…IL-6, a factor secreted by MSCs under inflammatory conditions, is critically required for MSC migration (49,50). MSCs inhibit inflammation and preserve vascular endothelial integrity in lungs (51). VEGF, a common factor associated with vascular growth, is involved in the rebuilding of vascular endothelial integrity (52) and increases the proliferation of MSCs (53).…”

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

“…MSCs and conditioned media from a co-culture of endothelial cells and MSCs have been reported to decrease endothelial paracellular permeability and protect against infl ammatory disruption of barrier function in vitro by mobilisation of adherens junction proteins to cell membranes 42 and limitation of binding of infl ammatory cells to the endothelium. 43 In vivo, by use of a rat model of controlled haemorrhage, MSCs were seen to stabilise endothelial cells in haemorrhagic shock, partly by preservation of adherens junction and tight junction proteins. 43 MSCs were also shown to decrease vascular permeability in a mouse model of caecal ligation and puncture.…”

“…43 In vivo, by use of a rat model of controlled haemorrhage, MSCs were seen to stabilise endothelial cells in haemorrhagic shock, partly by preservation of adherens junction and tight junction proteins. 43 MSCs were also shown to decrease vascular permeability in a mouse model of caecal ligation and puncture. 40 Finally, MSCs had benefi cial eff ects on endothelial cells in studies using ex-vivo perfused human lungs.…”

Anti-inflammatory effects of triptolide by inhibiting the NF-κB signalling pathway in LPS-induced acute lung injury in a murine model

“…This is caused by inflammation-related stimuli, primarily sepsis and pneumonia, which lead to leukocyte migration and overproduction of pro-inflammatory mediators, including interleukin (IL)-6, IL-8 and tumour necrosis factor-α (TNF-α) (3). ALI is a fatal disease that can cause persistent respiratory failure and multiorgan dysfunction, and patients with ALI may be dependent on mechanical ventilation (4)(5)(6). Although intensive care has been greatly improved, the mortality rate caused by ALI is between 40 and 70%, and ~200,000 individuals are affected by the condition in America every year.…”