Research into using mesenchymal stem cells (MSCs) to repair lung injury is associated with increased survival and has produced unexpected benefits in mouse models, said researcher and symposium co-chair Michael A. Matthay, M.D., in describing recent studies that could lead to future cell-based lung therapies.

In his introduction of the May 19 session, “Cells in Lung Injury and Repair of the Lung: Scientific and Translational Importance,” Dr. Matthay described the growing body of evidence pointing to the use of stem cells, lymphocytes and other cell types in the development of cell-based therapies for the lung.

The session was co-chaired by former ATS president Jo Rae Wright, Ph.D., and Teresa Barnes, who chairs the ATS Public Advisory Roundtable (PAR), which sponsored the symposium. Dr. Mark Looney also participated as a co-chair.

Dr. Matthay described MSC research that has been done at his University of California, San Francisco (UCSF) laboratory and elsewhere in the last decade, identifying possible therapeutic uses of stem cells in the lung. The most promising focused on components released by MSCs in the lung, including growth factors that could reduce endothelial and epithelial injury, and promote repair, he said.

Using stem cells isolated and cultured from mouse bone marrow, a colleague of Dr. Matthay, Naveen Gupta, M.D., showed that mice given high doses of endotoxin experienced higher survival rates when treated with MSCs than did control mice treated with fibroblasts or apoptotic stem cells. The research showed an increase in the number of anti-inflammatory cytokines in MSC-treated mice.

Next, Dr. Gianluca Samarani, M.D., in Dr. Matthay’s group used MSCs to treat mice infected with live E. coli pneumonia bacteria, and again survival compared to control was “excellent,” Dr. Matthay said. But the most exciting result from the mouse model came as a surprise to researchers.

“The unexpected discovery was that the number of organisms in the lung were reduced,” Dr. Matthay said. “So this is quite exciting to find that MSCs are associated with a reduction in the number of bacteria, and it turns out that this is a consistent finding and is emerging with other groups.”

In another important study conducted at Dr. Matthay’s lab, Jae Woo Lee, M.D., has used human MSCs in ex vivo perfused human donor lungs to test the effect of stem cells on alveolar fluid clearance and lung endothelial permeability. The human MSCs were effective when given by the intra-alveolar or the intra-venous route, Dr. Matthay said.

Bernard Lo, M.D., who chairs the UCSF Stem Cell Research Oversight Committee, presented an overview of ethical and policy issues involving the development and testing of cell-based therapies.

To illustrate ethical quandaries that researchers face today, Dr. Lo posed a question to his audience: How would they react to a patient considering stem cell transplantation in a foreign country for interstitial lung disease? Though patient marketing messages may promise a cure for illness, Dr. Lo reminded attendees that the use of stem cells abroad often lack a careful, unbiased, peer-reviewed scientific and ethical review.

“A careful scientific review is needed to avoid unintended adverse effects of stem cell transplantation, especially when impacting the immune system,” he said.

Research into the use of stem cells has brought into sharp focus the urgent need for clinical trials of potential new therapies. But research centers must think carefully about the patients recruited for such trials and make sure these patients truly give “informed” consent to their participation, Dr. Lo said.

Researchers must also make sure that patients in trials receive long-term clinical follow-up to make sure malignant transformation and acquired cytogenetic abnormalities don’t appear long after the trial ended, he said.

“Ethical and policy dilemmas are inherent in translational and clinical research, and in bringing new therapies to our patients,” Dr. Lo said. “Scientists, patients and the public need to be aware of these issues and think about how to resolve them.”

Landon S. King, M.D., began his presentation on research into lymphocytes and lung injury by citing studies that quantify the problem of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). Each year 190,000 American are affected by ALI/ARDS, which kills 75,000 per year, he said.

“To put that into context, if you add up all the projected deaths this year from breast and prostate cancers and from HIV, it’s about 79,000,” said Dr. King, who holds the David Marine professorship of pulmonary and critical care medicine at the Johns Hopkins School of Medicine in Baltimore.

Dr. King said he and his colleagues have been studying the mechanisms involved in the resolution of lung injury, primarily using a model of intratracheal lipopolysaccharide (LPS), in mice. What they found is a spike in the presence of lymphocytes in the transition from lung injury to repair.

“We became interested in the possibility that they (lymphocytes) were playing some role in this overall response,” he said.

Using lymphocyte-deficient mice, Dr. King and colleagues found that they exhibited an impaired resolution of LPS lung injury. His group became interested in a particular subset of CD4 cells and “we had compelling data to suggest that the activity we were interested in had been segregated in the CD4 compartment,” Dr. King said.

These CD4 cells, T regulatory (Treg) cells, became the focus of their investigation. The group has since worked to discover the source of beneficial interaction, or axis, between Treg cells and macrophages in aiding lung repair.

“We believe that Tregs, or a Treg-associated axis, may provide new targets for ALI therapy,” Dr. King said.

Jahar Bhattacharya, M.D., Ph.D., who is a professor of medicine at Columbia University, described his studies with MSCs in endotoxin-injured mice. He has found that the MSCs transfer mitochondria to the alveolar epithelium, which reduces lung injury by several pathways.

Using sophisticated imaging techniques in mouse lungs that have been injured with LPS, MSCs that are delivered intratracheally form intimate junctions with alveolar type II epithelial cells and deliver mitochondria and energy (ATP) to the epithelium. This transfer of mitochondria may explain part of the observed benefit of MSC therapy in the experimental acute lung injury studies.

Mark Looney, M.D., an assistant professor at UCSF, gave a presentation on the role of platelets and neutrophils in producing early lung endothelial injury in mice. Using mouse models of transfusion-related acute lung injury (TRALI) and acid-induced lung injury, Dr. Looney and co-workers at UCSF have discovered that platelets accumulate in acute lung injury (ALI) and interact closely with neutrophils.

In the TRALI model, injury and mortality can be significantly reduced with either platelet depletion or treatment with aspirin. Dr. Looney said that the role of platelets in acute inflammation and injury is not limited to the lung and is an exciting area of research that has the potential for new therapeutic approaches in patients with ALI.

Duncan Stewart, M.D., who is a professor of medicine at the University of Ottawa, presented results of experimental and clinical studies using stem cells as a therapeutic approach in sepsis and pulmonary hypertension.

Dr. Stewart and his team of researchers are conducting clinical trials using endothelial progenitor cells (EPCs) in patients with pulmonary arterial hypertension. EPCs are collected by pheresis from patients and transfected with a gene that increases the production of nitric oxide, which helps in the relaxation of blood vessels by reducing pulmonary vascular resistance.

In preliminary results, when the transfected EPCs are injected into patients with pulmonary hypertension in escalating doses, there is a reduction in pulmonary vascular resistance and an increased exercise capacity, especially in patients who are also receiving vasodilator therapy with sildenafil.

Dr. Stewart also presented results of treating mice with sepsis with MSCs transfected with angiopoietin 1, which is protective to the endothelium. When the mice with sepsis were treated with the angiopoietin 1-transfected MSCs, there was a reduction in acute lung injury and inflammation.