== Effect of MSCs on cellular responses and protein influx in the airspaces ofE. responsible for the antimicrobial activity of MSC CM against Gram-negative bacteria was the human cathelicidin antimicrobial peptide, hCAP-18/LL-37. Both m-RNA and protein expression data showed that this expression of LL-37 in MSCs increased after bacterial challenge. Using an in vivo mouse model ofE. colipneumonia, intratracheal administration of MSCs reduced bacterial growth (in colony-forming unit) in the lung homogenates and in the bronchoalveolar lavage (BAL) fluid, and administration of MSCs simultaneously with a neutralizing antibody to LL-37 resulted in a decrease in bacterial clearance. In addition, the BAL itself from MSC-treated mice had a greater antimicrobial activity in comparison with the BAL of phosphate buffered saline (PBS)-treated mice. Human bone marrow-derived MSCs possess direct antimicrobial activity, which is usually mediated in part by the secretion of human cathelicidin hCAP-18/LL-37. Keywords:Acute lung injury/acute respiratory distress syndrome, Antimicrobial peptides/proteins,E. colipneumonia, LL-37, Mesenchymal stem cells == Introduction == The innate immune system provides the first line of defense against microbial infections. Among the key effector molecules responsible for bacterial killing are antimicrobial proteins and polypeptides, which comprise a diverse group, including lysozyme, lactoferrin, secretory leucoprotease inhibitor, and defensins, all of which are able to kill microorganisms [1]. The cathelicidin family is one of the main antimicrobial peptide families in mammals [2]. Peptides belonging to the cathelicidin family are either constitutively produced or induced on stimulation [3,4]. Cathelicidins as well as the majority of known antimicrobial peptides exert their microbicidal activity through the disruption of the integrity of bacterial membranes [5]. In humans, the cathelicidin family of antimicrobial peptides 3-Butylidenephthalide 3-Butylidenephthalide is usually represented by a 4 kDa peptide, hCAP-18/LL-37, that is mainly produced by phagocytic leukocytes and epithelial cells, but it is also expressed in the bone marrow [6] and by mesenchymal stem cells (MSCs) [7]. LL-37 has a wide range of biological activities including direct killing of microorganisms, chemotaxis and chemokine induction, and regulation of inflammatory responses, as well as angiogenic, antiapoptotic, aids in horizontal DNA intracellular transfer, and wound healing effects [8,9]. MSCs are multipotent adult stem cells found in the bone marrow and other anatomic niches, which have the capacity to differentiate into multiple cell types such as osteoblasts, adipocytes, and chondroblasts under in vitro conditions [10,11]. Bone marrow (BM)-derived MSCs reside near the sinusoids and function as support cells for hematopoietic stem cells, perhaps providing some protection against microbial invasion. Although it is usually well established that MSCs have toll-like receptor (TLR) receptors [1215] and are involved in inflammatory responses [16], little is known about their role in the innate immune system. Acute lung injury (ALI) is usually a major cause of acute respiratory failure in critically ill patients. Bacterial pneumonia is the most common cause of ALI [17]. Recent studies have exhibited that BM-derived MSCs reduce lung injury in experimental models of lipopolysaccharide (LPS)-induced ALI in mouse [18,19] and in an ex vivo-perfused human lung [20]. In addition, GPX1 other 3-Butylidenephthalide in vitro and in vivo studies have provided evidence for the beneficial effects of MSCs in the treatment of LPS- or bacteria-induced sepsis. In two mouse models of sepsis following cecal ligation and puncture (CLP), i.v. MSCs reduced total bacterial counts in the blood and peritoneal fluid [21,22]. These survival benefits were explained in part by the immunomodulatory properties of MSCs, but the actual mechanism of enhanced bacterial clearance was not clearly identified. Although a recent publication by Mei et al. [23] showed that this improvement in bacterial clearance in MSC-treated septic mice following CLP could be in part explained by enhanced phagocytic activity of host immune cells, it is not known yet whether human BM-derived MSCs possess direct antimicrobial activity. Thus, the primary hypothesis for these studies was that human MSCs might express direct antimicrobial activity through the secretion of antimicrobial peptides. We examined.
