**3. Mesenchymal stem cell therapy for sepsis and acute respiratory distress syndrome**

The complex pathophysiology of sepsis and also of ARDS requires a therapy with a wide range of properties. The heterogeneity of the host response in front of sepsis or ARDS makes it difficult to find a proper drug that works as a therapy. Stem cells are potential therapeutic agents with a diverse spectrum of action and can act at different levels of the pathophysiology of ARDS or sepsis, non only treating inflammation, moreover affecting coagulation, enhancing antimicrobial effect, modulating the innate and adaptive immune response, and reducing endothelium permeability and edema.

MSCs can be administered intravenously, but then only a small percentage of injected cells arrive to the injury site. Usually, MSCs get trapped into the lung's microvasculature, and after some hours, they are engulfed by macrophages and they disappear. It is well known that cells do not engraft into the tissue and their primary action mechanism is the secretion of soluble factors with therapeutic properties.

MSCs release into the extracellular media bioactive cytokines, chemokines, angiogenic factors, and/or growth factors. Moreover, it has been described that MSCs also release extracellular vesicles with bioactive compounds. Extracellular vesicles are small vesicles made by a phospholipid bilayer and encapsulate proteins, lipids, or miRNAs or other compounds that are protected from the media and can be phagocytosed by other cells and act on them. Nowadays, the use of extracellular vesicles to target specific cells is also a raising up therapy competing with cell therapies; however, there is still a lot to define about the secretome of the MSC to be able to mimic its therapeutic effects.

All these factors directly secreted to the media or inside extracellular vesicles regulate intracellular pathways from different cells and can act on the innate and adaptive immune system. The different effects or mechanisms are described in the following sections and in **Figure 1**.

### **3.1 Effects on the innate immune system**

Inflammation is one of the main drivers of ARDS and sepsis pathogenesis. During ARDS, the injury of the lung endothelium and epithelium is producing a recruitment of pro-inflammatory cells such as neutrophils and monocytes into the alveolar space. These pro-inflammatory cells release several pro-inflammatory cytokines, for example, TNF-α, IL-1β, and IL-6 [52–54]. Moreover, neutrophils are secreting several ROS enhancing the damage of the endothelium and epithelial layers propagating the damage [55–57].

*Innovations in Cell Research and Therapy*

reducing the graft-versus-host disease [20–22].

**2.3 Endothelial progenitor cells (EnPC)**

sepsis and ARDS [31–34].

the tissues [35, 36].

genicity potential.

**2.5 Mesenchymal stem cells (MSC)**

blood, placenta, adipose tissue, lung, and bone marrow.

and chondroblasts) in *in vitro* conditions [40].

**2.4 Epithelial progenitor cells (EpPC)**

pro-angiogenic factors and generate a new vessel [28].

reprogramming and finally are able to express four transcription factors such as Ocet3/4, Sox2, Klf-4, and c-Myc. They grow indefinitely and differentiate into all cell types of the human body, and also they can be obtained in autologous way

The main problem is that the dedifferentiation and reprogramming have low efficiency, and their genomic modification could create associated problems that until now are unknown or have not been studied and have a high tumorigenicity risk [23–25]. The potential applications of iPSCs in sepsis and ARDS are many [26, 27].

The endothelial damage is one of the main hallmarks of ARDS, and EnPCs have the ability to regenerate endothelial cells and could have an unlimited role in repairing the damaged endothelium. EnPCs have been defined as circulating cells that have ability to adhere to the endothelium at sites of hypoxia and ischemia secreting

EnPCs express hematopoietic surface cell markers such as CD34. However, the

Very few pre-clinical studies have been published, which have used EnPCs in

Some epithelial progenitors of the lung alveolar compartment have also been identified, but their isolation is really difficult and the number of cells that could be

EpPCs are specified during development in each tissue and are highly regulated by epithelial-mesenchymal interactions. Different tissues have different EpPCs with small adjustments in their function; however, their maintenance, activation, and differentiation are regulated by the same pathways between all

The use of alveolar-epithelial type II cells (AE2C) for the treatment of ARDS has been demonstrated; these cells are more differentiated than EpPCs, but still can proliferate and differentiate into alveolar-epithelial type I cell, that are the complete differentiated cells in the lung epithelia. AE2C cells can only be isolated from the lungs of organ donors and may have problems in graft-versus-host disease [37–39]. The isolation of AE2C is laborious, but they have less ethical problems and tumori-

MSCs are the best described cells and mostly used as a cell therapy. MSCs are multipotent cells that have been isolated from several tissues such as umbilical cord

The International Society of Cellular Therapy defined that MSCs should follow the three criteria: (1) MSCs must be adherent to plastic; (2) MSCs must express some cell surface markers, such as CD105, CD90, and CD73, but must not express other markers, including CD45, CD34, CD14, or CD11b; and (3) MSCs must have the capacity to differentiate into mesenchymal lineages (osteoblasts, adipocytes,

role, isolation, and identification of these cells are not completely elucidated. EnPCs can be useful as a regenerative instrument to treat several vascular diseases, but the ability to adhere to the endothelium at sites of hypoxia and ischemia

secretes pro-angiogenic factors and generates a new vessel [29, 30].

obtained is really low. EpPCs might be useful in the treatment of ARDS.

**6**

**Figure 1.** *Potential mechanisms of the cell therapies.*

During sepsis, the infection activates TLR4, which leads to the activation of MyD88 and NF-kb and the transcription of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. After the first hours following the infection, there is a specific storm of cytokines [58].

MSCs have the ability to modulate the immune response and secrete several anti-inflammatory cytokines such as IL-4, IL-10, or IL-13 [59]. Furthermore, they regulate inflammation using different strategies and acting on different cells, which are described in the following sections.

### *3.1.1 Effects on humoral immune response*

Numerous studies proved that MSCs decrease the pro-inflammatory cytokine response (TNF-α, IFN-γ, and IL-1α, -1β, -6, -12, and -17). They promote this effect while increasing concentrations of the anti-inflammatory agents, including IL-1 receptor antagonist (IL-1Ra), IL-10, tumor necrosis factor-inducible gene 6 protein (TSG-6), cyclooxygenase-2 (COX-2), insulin-like growth factor 1 (IGF-1), and prostaglandin-E2 (PGE2) [60, 61].

All these factors act on different cells; for example, IL-1Ra is able to reduce the production of inflammatory TNF-α in macrophages and also inhibits helper-T lymphocytes activation. TSG-6 has a potent anti-inflammatory effect acting in macrophages and polarizing them from a pro- to an anti-inflammatory phenotype while reducing the secretion of inflammatory chemokines by these cells. IGF-1 has been described as an anti-apoptotic compound, and during sepsis and ARDS, less apoptosis of the endothelium and epithelium cells reduces the damage and the associated inflammation [62, 63].

### *3.1.2 Effects on the inflammasome*

The inflammasome is a multiprotein intracellular oligomer that detects pathogenic microorganisms and other factors and activates an inflammatory response. Inflammasome activates caspase-1 and caspase-1 cleaves the precursor cytokines

**9**

*Current Status of Stem Cell Therapy for Sepsis and Acute Respiratory Distress Syndrome*

NLRP3 activation moderates cell death and organ dysfunction [65].

is produced through the stimulation of TLR-3 by MSCs.

depletion abolishes the protective effect of MSCs [55, 69, 70].

functions, and participation in several metabolic pathways [71, 72].

*3.1.4 Effects on monocyte/macrophage response*

strated to be important to damage resolution.

pro-IL-1β and pro-IL-18, generating the biologically active cytokines IL-1β and IL-18, respectively. Caspase 1 also activates following compounds derived from the host innate immune system that can lead to pyropotosis (an inflammatory form of cell death) [64]. Generally, myeloid cells such as neutrophils, monocytes, and macrophages are expressing inflammasome proteins such as pattern-recognition receptors (PRRs), toll-like receptors (TLR), or C-type lectin receptors in their membrane. NLRP3 is the best characterized and versatile inflammasome and is mainly expressed by myeloid lineage cells and stimulated by the activation of TLR and other signals [64, 65].

MSCs can regulate the NLRP3 inflammasome activation through the secretion of PGE2 that leads to an increase in IL-10 production by macrophages. The decrease in

Sepsis is associated with neutropenia, and it has been shown that MSCs are able to increase the neutrophil counts after their administration [66, 67]. The activity and survival of neutrophils were also increased in the lung during ARDS; this effect

During sepsis and ARDS, the injury or pathogen activates some recognition receptors that promote activated neutrophils recruitment. Neutrophils release some antimicrobial compounds and produce some traps to eliminate the pathogen. During sepsis, the general infection produces an overactivation of the neutrophils that migrate to inflamed and noninflamed tissue and can lead to an organ dysfunction [68].

Several pre-clinical studies have demonstrated that MSCs are able to modify neutrophils behavior, maintaining their bactericidal function but reducing the host injury. In pre-clinical sepsis models, MSC therapy diminishes neutrophil infiltration into several organs such as lung, liver, gut, and kidney, reducing injury and improving organ function. Besides, MSCs augment neutrophil-mediated phagocytosis, improving the clearance of bacteria. It has been demonstrated that the protective effect of MSCs in systemic sepsis is clearly mediated by neutrophils, because their

Monocytes and macrophages are present in practically all tissues. They have a wide range of functions like maintenance of the tissue homeostasis, immunologic

It is well known that, in the course of sepsis and ARDS, macrophages get dysfunction and are not able to perform their activity as usual. Several groups focus in the use of MSCs as modulator of macrophages activity [73, 74]. Tissue resident macrophages and also circulating monocytes that migrate into the tissue and convert to macrophages can polarize to different phenotypes. Pro-inflammatory or M1 macrophages produce several pro-inflammatory cytokines and are involved in the elimination of pathogens. Anti-inflammatory/reparative or M2 macrophages secrete more anti-inflammatory compounds and are involved in the clearance of apoptotic cells. Alteration of M1 macrophages to a M2 phenotype has been demon-

MSCs have the ability to secrete several factors that polarize macrophages to a M2 phenotype, promoting a resolution phase, increasing phagocytic activity, and decreasing inflammation. It has been described that macrophages secrete PGE-2 that is able to increase the production of IL-10, SOCS-3, TGF-β, TSG-6, and others [60, 75]. All these factors are able to reduce the recruitment/migration of pro-inflammatory cells into the tissue, preventing organ dysfunction and also

*DOI: http://dx.doi.org/10.5772/intechopen.86108*

*3.1.3 Effects on neutrophil response*

### *Current Status of Stem Cell Therapy for Sepsis and Acute Respiratory Distress Syndrome DOI: http://dx.doi.org/10.5772/intechopen.86108*

pro-IL-1β and pro-IL-18, generating the biologically active cytokines IL-1β and IL-18, respectively. Caspase 1 also activates following compounds derived from the host innate immune system that can lead to pyropotosis (an inflammatory form of cell death) [64].

Generally, myeloid cells such as neutrophils, monocytes, and macrophages are expressing inflammasome proteins such as pattern-recognition receptors (PRRs), toll-like receptors (TLR), or C-type lectin receptors in their membrane. NLRP3 is the best characterized and versatile inflammasome and is mainly expressed by myeloid lineage cells and stimulated by the activation of TLR and other signals [64, 65].

MSCs can regulate the NLRP3 inflammasome activation through the secretion of PGE2 that leads to an increase in IL-10 production by macrophages. The decrease in NLRP3 activation moderates cell death and organ dysfunction [65].

### *3.1.3 Effects on neutrophil response*

*Innovations in Cell Research and Therapy*

specific storm of cytokines [58].

*Potential mechanisms of the cell therapies.*

**Figure 1.**

are described in the following sections.

*3.1.1 Effects on humoral immune response*

prostaglandin-E2 (PGE2) [60, 61].

associated inflammation [62, 63].

*3.1.2 Effects on the inflammasome*

During sepsis, the infection activates TLR4, which leads to the activation of MyD88 and NF-kb and the transcription of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. After the first hours following the infection, there is a

MSCs have the ability to modulate the immune response and secrete several anti-inflammatory cytokines such as IL-4, IL-10, or IL-13 [59]. Furthermore, they regulate inflammation using different strategies and acting on different cells, which

Numerous studies proved that MSCs decrease the pro-inflammatory cytokine response (TNF-α, IFN-γ, and IL-1α, -1β, -6, -12, and -17). They promote this effect while increasing concentrations of the anti-inflammatory agents, including IL-1 receptor antagonist (IL-1Ra), IL-10, tumor necrosis factor-inducible gene 6 protein (TSG-6), cyclooxygenase-2 (COX-2), insulin-like growth factor 1 (IGF-1), and

All these factors act on different cells; for example, IL-1Ra is able to reduce the production of inflammatory TNF-α in macrophages and also inhibits helper-T lymphocytes activation. TSG-6 has a potent anti-inflammatory effect acting in macrophages and polarizing them from a pro- to an anti-inflammatory phenotype while reducing the secretion of inflammatory chemokines by these cells. IGF-1 has been described as an anti-apoptotic compound, and during sepsis and ARDS, less apoptosis of the endothelium and epithelium cells reduces the damage and the

The inflammasome is a multiprotein intracellular oligomer that detects pathogenic microorganisms and other factors and activates an inflammatory response. Inflammasome activates caspase-1 and caspase-1 cleaves the precursor cytokines

**8**

Sepsis is associated with neutropenia, and it has been shown that MSCs are able to increase the neutrophil counts after their administration [66, 67]. The activity and survival of neutrophils were also increased in the lung during ARDS; this effect is produced through the stimulation of TLR-3 by MSCs.

During sepsis and ARDS, the injury or pathogen activates some recognition receptors that promote activated neutrophils recruitment. Neutrophils release some antimicrobial compounds and produce some traps to eliminate the pathogen. During sepsis, the general infection produces an overactivation of the neutrophils that migrate to inflamed and noninflamed tissue and can lead to an organ dysfunction [68].

Several pre-clinical studies have demonstrated that MSCs are able to modify neutrophils behavior, maintaining their bactericidal function but reducing the host injury.

In pre-clinical sepsis models, MSC therapy diminishes neutrophil infiltration into several organs such as lung, liver, gut, and kidney, reducing injury and improving organ function. Besides, MSCs augment neutrophil-mediated phagocytosis, improving the clearance of bacteria. It has been demonstrated that the protective effect of MSCs in systemic sepsis is clearly mediated by neutrophils, because their depletion abolishes the protective effect of MSCs [55, 69, 70].

### *3.1.4 Effects on monocyte/macrophage response*

Monocytes and macrophages are present in practically all tissues. They have a wide range of functions like maintenance of the tissue homeostasis, immunologic functions, and participation in several metabolic pathways [71, 72].

It is well known that, in the course of sepsis and ARDS, macrophages get dysfunction and are not able to perform their activity as usual. Several groups focus in the use of MSCs as modulator of macrophages activity [73, 74]. Tissue resident macrophages and also circulating monocytes that migrate into the tissue and convert to macrophages can polarize to different phenotypes. Pro-inflammatory or M1 macrophages produce several pro-inflammatory cytokines and are involved in the elimination of pathogens. Anti-inflammatory/reparative or M2 macrophages secrete more anti-inflammatory compounds and are involved in the clearance of apoptotic cells. Alteration of M1 macrophages to a M2 phenotype has been demonstrated to be important to damage resolution.

MSCs have the ability to secrete several factors that polarize macrophages to a M2 phenotype, promoting a resolution phase, increasing phagocytic activity, and decreasing inflammation. It has been described that macrophages secrete PGE-2 that is able to increase the production of IL-10, SOCS-3, TGF-β, TSG-6, and others [60, 75]. All these factors are able to reduce the recruitment/migration of pro-inflammatory cells into the tissue, preventing organ dysfunction and also

decreasing the production of pro-inflammatory cytokines such as TNF-α or IFN-γ by macrophages [76].

Furthermore, complement activation pathway is also upregulated by MSCs infusion, what leads to a more efficient clearance of pathogens. MSCs, as we had previously described, secrete KGF that also promotes a M2 phenotype and can transfer mitochondria to macrophages, also reducing their pro-inflammatory phenotype [73, 77]. During ARDS, it has been shown that MSCs attenuate the damage induced by bacteria or LPS through the inhibition of Wnt/β-catenin pathway. The effects of MSCs on the macrophage activation varies quite a lot depending on the organ, the stage of the disease, and the steady-state of these macrophages when MSCs are infused.

### **3.2 Effects on adaptive immune response**

In several diseases, there is an enhanced activation and proliferation of T and B cells, and this is also happening during sepsis. MSCs have the ability to diminish this cell activity and their proliferation [78, 79].

Explicitly, it has been shown that MSCs inhibit effector T-cell activation and can increase regulatory T-cell numbers, while suppressing propagation of CD4+ T-helper cells, CD8+ cytotoxic T lymphocytes, and natural killer cells [80, 81]. This effect is mediated through the secretion of PGE-2 and TGF-β1 [82]. Moreover, MSCs promote the formation of CD8+ regulatory T cells that might decrease cytotoxicity caused by cytotoxic lymphocytes [83, 84].

Regulatory T cells are a subclass of T cells, which functions in modulating the immune system and maintaining the antigen tolerance. These cells are able to limit inflammation and reduce organ dysfunction in sepsis, and MSCs have the capacity to regulate regulatory-T cell function [81, 85]. It has been verified that regulatory T cells subset is necessary to eliminate bacteria during infections.

MSCs induce regulatory T cells promoting their efficiency and enhancing sepsis or ARDS resolution [86, 87].

It has also been reported that MSCs modified the activity of other cells from the adaptive immune system such as NK, regulatory B cells, and dendritic cells.

### **3.3 Antibiotic properties**

MSCs have been reported to have antibiotic/antimicrobial effects. They reduced bacterial levels in bronchoalveolar lavage, blood, spleen, and lung tissue. Generally, the antimicrobial effect of MSCs is due to their effect on host immune cells. MSCs have the ability to increase the phagocytic capacity of the host immune cells such as macrophages, monocytes, dendritic cells, and neutrophils [54, 73, 88]. It has been shown that this effect is produced through the production of keratinocyte growth factor (KGF) or also named fibroblast growth factor 7 (FGF7) [62, 69, 89].

Besides, MSCs are producing other factors with antibiotic properties per se. For example, in some pre-clinical models, it has been described that mouse MSCs secrete lipocalin-2, also known as neutrophil gelatinase-associated lipocalin (NGAL), which limits bacterial growth by iron sequestration. Human MSCs secrete LL-37, also known as cathelicidin antimicrobial peptide 18, described as antimicrobial peptide [90]. Patients with a high level of LL-37 were more likely to survive to a strong infection.

### **3.4 Antiapoptotic effects**

During sepsis and ARDS, the apoptosis of endothelial, epithelial, and immune cells is one of the main descriptors of the severity of the disease. MSC therapy has been confirmed that it is able to limit the apoptosis of host cells.

**11**

*Current Status of Stem Cell Therapy for Sepsis and Acute Respiratory Distress Syndrome*

MSCs or their supernatants and also *in vivo* where resident macrophages have presented less apoptosis [91, 92]. It seems that antiapoptotic effect of MSCs does not require cell-cell contact, and IL-6 and FGF7 have been described as the main

The antiapoptotic capacity has been tested *in vitro* incubating neutrophils with

The role of MSCs in the decrease of monocytes, macrophages, and neutrophils apoptosis is directly associated with an increase in the clearance of bacteria and also

The endothelial and epithelial injury is a crucial characteristic of sepsis and ARDS. Throughout sepsis and ARDS, the barrier function of the endothelium and epithelium is destroyed due to the loss of their integrity and the disruption of the

MSCs have been described that they are able to decrease permeability and decrease the disturbance of the membrane, promoting the production of tight junction proteins and limiting the binding of inflammatory cells to the endothelium. It seems from some *in vitro* studies that the preserving effect of MSCs on permeability is due to the secretion of IL-1Ra and PGE-2, which decrease inflammation and

MSCs work by multiple mechanisms and can exert their effect through cell-cell contact, secreting several factors directly to the media or through the release of

It seems that during sepsis and ARDS the MSC are not really engrafted in any tissue; however, it has been demonstrated that cells migrate to the site of the injury and they are retained there for a while. It has been shown that some effects are produced through cell-cell contact between MSCs and alveolar epithelial cells mainly to regulate endothelial integrity creating some junctions and transferring mitochondria or other cellular products with therapeutic effect [58, 60, 89].

In the last sections, we reviewed the effects of MSCs through the secretion of several factors such as antimicrobial peptides, antiapoptotic effectors, or immuno-

Besides, MSCs release extracellular vesicles, which encapsulate several cellular components, including mitochondria and gene products such as miRNAs and mRNAs. Moreover, it has been described that some extracellular vesicles can also encapsulate lipids and proteins. Several studies have described the delivery of miR-223 that is transfer to macrophages and cardiomyocytes and reduces their inflammatory response. Also, the mRNA from KGF has also been detected inside these extracellular vesicles, producing its effect in the endothelium and epithelium

The encouraging preclinical data suggest that cell-based therapies capable of simultaneously affecting multiple processes constitute a promising new approach to sepsis and ARDS treatment [100]. MSCs can be efficiently cultured from bone marrow, umbilical cord blood, adipose tissue, and other sources and have a low

*DOI: http://dx.doi.org/10.5772/intechopen.86108*

can explain the antibiotic properties of MSCs [69].

reduce endothelial and epithelial cell apoptosis [94–96].

**4. Mechanisms by which MSCs exert their effects**

drivers of this effect.

extracellular vesicles.

modulatory mediators.

**5. Clinical trials**

and enhancing their repair [97–99].

**3.5 Regulation of permeability**

junction proteins between cells [1, 93].

*Current Status of Stem Cell Therapy for Sepsis and Acute Respiratory Distress Syndrome DOI: http://dx.doi.org/10.5772/intechopen.86108*

The antiapoptotic capacity has been tested *in vitro* incubating neutrophils with MSCs or their supernatants and also *in vivo* where resident macrophages have presented less apoptosis [91, 92]. It seems that antiapoptotic effect of MSCs does not require cell-cell contact, and IL-6 and FGF7 have been described as the main drivers of this effect.

The role of MSCs in the decrease of monocytes, macrophages, and neutrophils apoptosis is directly associated with an increase in the clearance of bacteria and also can explain the antibiotic properties of MSCs [69].

### **3.5 Regulation of permeability**

*Innovations in Cell Research and Therapy*

**3.2 Effects on adaptive immune response**

cell activity and their proliferation [78, 79].

or ARDS resolution [86, 87].

**3.3 Antibiotic properties**

**3.4 Antiapoptotic effects**

cytotoxicity caused by cytotoxic lymphocytes [83, 84].

cells subset is necessary to eliminate bacteria during infections.

by macrophages [76].

decreasing the production of pro-inflammatory cytokines such as TNF-α or IFN-γ

Furthermore, complement activation pathway is also upregulated by MSCs infusion, what leads to a more efficient clearance of pathogens. MSCs, as we had previously described, secrete KGF that also promotes a M2 phenotype and can transfer mitochondria to macrophages, also reducing their pro-inflammatory phenotype [73, 77]. During ARDS, it has been shown that MSCs attenuate the damage induced by bacteria or LPS through the inhibition of Wnt/β-catenin pathway. The effects of MSCs on the macrophage activation varies quite a lot depending on the organ, the stage of the disease, and the steady-state of these macrophages when MSCs are infused.

In several diseases, there is an enhanced activation and proliferation of T and B cells, and this is also happening during sepsis. MSCs have the ability to diminish this

Explicitly, it has been shown that MSCs inhibit effector T-cell activation and can increase regulatory T-cell numbers, while suppressing propagation of CD4+ T-helper cells, CD8+ cytotoxic T lymphocytes, and natural killer cells [80, 81]. This effect is mediated through the secretion of PGE-2 and TGF-β1 [82]. Moreover, MSCs promote the formation of CD8+ regulatory T cells that might decrease

Regulatory T cells are a subclass of T cells, which functions in modulating the immune system and maintaining the antigen tolerance. These cells are able to limit inflammation and reduce organ dysfunction in sepsis, and MSCs have the capacity to regulate regulatory-T cell function [81, 85]. It has been verified that regulatory T

MSCs induce regulatory T cells promoting their efficiency and enhancing sepsis

It has also been reported that MSCs modified the activity of other cells from the

MSCs have been reported to have antibiotic/antimicrobial effects. They reduced bacterial levels in bronchoalveolar lavage, blood, spleen, and lung tissue. Generally, the antimicrobial effect of MSCs is due to their effect on host immune cells. MSCs have the ability to increase the phagocytic capacity of the host immune cells such as macrophages, monocytes, dendritic cells, and neutrophils [54, 73, 88]. It has been shown that this effect is produced through the production of keratinocyte growth factor (KGF) or also named fibroblast growth factor 7 (FGF7) [62, 69, 89].

Besides, MSCs are producing other factors with antibiotic properties per se. For example, in some pre-clinical models, it has been described that mouse MSCs secrete lipocalin-2, also known as neutrophil gelatinase-associated lipocalin (NGAL), which limits bacterial growth by iron sequestration. Human MSCs secrete LL-37, also known as cathelicidin antimicrobial peptide 18, described as antimicrobial peptide [90]. Patients with a high level of LL-37 were more likely to survive to a strong infection.

During sepsis and ARDS, the apoptosis of endothelial, epithelial, and immune cells is one of the main descriptors of the severity of the disease. MSC therapy has

been confirmed that it is able to limit the apoptosis of host cells.

adaptive immune system such as NK, regulatory B cells, and dendritic cells.

**10**

The endothelial and epithelial injury is a crucial characteristic of sepsis and ARDS. Throughout sepsis and ARDS, the barrier function of the endothelium and epithelium is destroyed due to the loss of their integrity and the disruption of the junction proteins between cells [1, 93].

MSCs have been described that they are able to decrease permeability and decrease the disturbance of the membrane, promoting the production of tight junction proteins and limiting the binding of inflammatory cells to the endothelium. It seems from some *in vitro* studies that the preserving effect of MSCs on permeability is due to the secretion of IL-1Ra and PGE-2, which decrease inflammation and reduce endothelial and epithelial cell apoptosis [94–96].
