Stem Cells in Sepsis and Acute Lung Injury

doi:10.1097/MAJ.0b013e3181f30dee

The American Journal of the Medical Sciences

Volume 341, Issue 4, April 2011, Pages 325-332

https://doi.org/10.1097/MAJ.0b013e3181f30dee Get rights and content

Abstract

Introduction

Critical illnesses continue to be major causes of morbidity and mortality worldwide. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the use of stem cells in sepsis and acute lung injury as prognostic biomarkers and also as a potential for exogenous cell-based therapy.

Methods

A directed search of the medical literature was done using PubMed and OviD to evaluate topics related to pathophysiology of sepsis and acute lung injury, in addition to the characterization and utilization of stem cells in these diseases.

Conclusions:

Stem cells have shown significant promise in the field of critical care medicine both for prognostication and treatment strategies. Although recent studies have been done to describe the mechanistic pathways of stem cells in critical illness, further investigation is necessary to fully delineate the mechanisms behind a stem cell’s immunomodulatory characteristics and its ability to mobilize and engraft in tissues.

Section snippets

Sepsis as a Prototypical Critical Illness

Sepsis is a significant public health problem, affecting more than 700,000 people every year in the United States. In the United States, sepsis is a leading cause of death in the intensive care unit (ICU), and it is the 10th leading cause of death overall.6., 22., 23. Sepsis is an acute inflammatory response to an infection, and the severity of the inflammatory response may cause organ dysfunction, which is a primary determinant of survival.¹ The development of organ dysfunction, such as

STEM CELL CLASSIFICATION

Stem cells have the capacity for extensive self-renewal with the potential to change into cells of multiple lineages.⁵¹ Individual stem cells self-generate and undergo continuous cell formation, leading to a succession of cells that have progressively less capacity for self-generation until ultimately a lineage-committed cell is formed. Until recently, the beneficial effects of stem cells were mostly attributed to their ability to incorporate into tissue (engraftment) and repair injured areas.

STEM CELLS AS PROGNOSTIC BIOMARKERS

The last several years have seen a significant increase in the amount of preclinical and clinical data regarding the predictive potential of stem cells in critical illness.

THERAPEUTIC POTENTIAL OF STEM CELLS

An assortment of clinical trials have used stem cells in diseases such as cardiovascular diseases,49., 61. heart failure,⁷³ pulmonary hypertension,⁷⁴ graft-versus-host disease¹⁵ and cerebrovascular disease.⁷⁵ However, until recently, MSCs and EPCs had not been extensively studied in critical illness.

CONCLUSION

Considerable progress has been made in the last decade regarding management strategies in critical illnesses, specifically sepsis and ALI/ARDS. Fluid resuscitation in severe sepsis and septic shock has hit a new milestone,⁵ whereas the use of lung protective ventilation with tidal volume and plateau pressure limits has reduced mortality substantially in ALI/ARDS.³ However, despite these recent advances, more work needs to be done to (1) further improve morbidity, it is now apparent that

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Mesenchymal stem cells (MSCs) have been widely documented for their potential role in the treatment of various clinical disorders, including acute lung injury (ALI). ALI represents a clinical syndrome associated with histopathological diffuse alveolar damage. Recent evidence has demonstrated that exosomes derived from MSCs may serve as a reservoir of anti-apoptotic microRNAs (miRs) conferring protection from certain diseases. Hence, the current study was performed with the aim of investigating whether MSCs-exosomal miR-30b-3p could confer protection against ALI. A bioinformatic analysis and a dual luciferase assay were initially performed to verify that SAA3 was highly-expressed in ALI which was confirmed to be a target gene of miR-30b-3p. Next, the lipopolysaccharide (LPS)-treated type II alveolar epithelial cells (AECs) (MLE-12) were transfected with mimics or inhibitors of miR-30b-3p, or sh-SAA3. It was revealed that LPS induced AEC apoptosis, which could be inhibited by overexpressing miR-30b-3p by down-regulating the expression of SAA3. After co-culture of PKH26-labeled exosomes with MLE-12 cells, we found that the number of PKH26-labeled exosomes endocytosed by MLE-12 cells gradually increased. Furthermore, the LPS-treated MLE-12 cells co-cultured with MSC-exosomes overexpressing miR-30b-3p exhibited increased miR-30b-3p, decreased SAA3 level, as well as increased cell proliferation, accompanied by diminished cell apoptosis in LPS-treated MLE-12 cells. Finally, the protective effect of MSCs-exosomal miR-30b-3p on the AECs in vivo was investigated in an ALI mouse model with tail vein injection of MSC-exosomes with elevated miR-30b-3p, showing that overexpression of miR-30b-3p in MSC-exosomes conferred protective effects against ALI. Taken together, these findings highlighted the potential of MSC-exosomes overexpressing miR-30b-3p in preventing ALI. The exosomes derived from MSCs hold potential as future therapeutic strategies in the treatment of ALI.
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Review ArticleStem Cells in Sepsis and Acute Lung Injury

Abstract

Introduction

Methods

Conclusions:

Section snippets

Sepsis as a Prototypical Critical Illness

STEM CELL CLASSIFICATION

STEM CELLS AS PROGNOSTIC BIOMARKERS

THERAPEUTIC POTENTIAL OF STEM CELLS

CONCLUSION

Chest

Chest

Cell

Blood

Blood

Cell Stem Cell

Exp Cell Res

Cytotherapy

Exp Hematol

Blood

Blood

Blood

Am J Pathol

J Am Coll Cardiol

Biochem Pharmacol

Respir Res

Transplant Proc

The acute respiratory distress syndrome

N Engl J Med

Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network

N Engl J Med

Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med

Early goal-directed therapy in the treatment of severe sepsis and septic shock

N Engl J Med

The epidemiology of sepsis in the United States from 1979 through 2000

N Engl J Med

Incidence and outcomes of acute lung injury

N Engl J Med

Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis StudyGroup

JAMA

Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study

JAMA

Neutrophils and acute lung injury

Crit Care Med

Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome

Nat Med

Biological markers of acute lung injury: prognostic and pathogenetic significance

Am J Respir Crit Care Med

Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice

J Immunol

Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease

Transplantation

Bone marrow-derived mesenchymal stem cells in repair of the injured lung

Am J Respir Cell Mol Biol

Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing

PLoS One

Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice

Am J Physiol Lung Cell Mol Physiol

Increased circulating endothelial progenitor cells are associated with survival in acute lung injury

Am J Respir Crit Care Med

Increased circulating endothelial progenitor cells in septic patients: correlation with survival

Crit Care Med

Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study

Intensive Care Med

Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy

Ann Intern Med

Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis

JAMA

Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units

Intensive Care Med

Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland

Crit Care Med

Sepsis in European intensive care units: results of the SOAP study

Crit Care Med

Treating sepsis: an update on the latest therapies, part 1

Infect Med

The physiological disturbances produced by endotoxins

Annu Rev Physiol

Mechanisms in the production of tissue damage and shock by endotoxins

Review Article
Stem Cells in Sepsis and Acute Lung Injury