Key protein discoveries could lead to new lung repair therapies for children, adults

Children's Hospital Los AngelesAug 5 2011

A team at The Saban Research Institute of Children's Hospital Los Angeles has made crucial discoveries about the role of key proteins in wound healing in the tiny air sacs in the lungs known as "alveoli" that could lead to new therapies for children and adults.

"Understanding the composition of the alveolar microenvironment at the protein level may allow us to design treatments to enhance repair of the alveolar surface," said David Warburton, DSc, MD, director of Developmental Biology and Regenerative Medicine at The Saban Research Institute.

The study—"The Milieu of Damaged AEC2 Stimulates Alveolar Wound Repair By Endogenous and Exogenous Progenitors"— earned the investigators a featured story in the American Journal of Respiratory Cell and Molecular Biology.

The research team looked at a little-studied component of the lungs—damaged alveolar epithelial cells type II (AEC2). These cells lie in the corners of the alveoli, which is comprised of millions of tiny air sacs where the exchange of oxygen and carbon dioxide takes pace. Cumulatively, the alveoli have a vast surface area, equivalent in size to a tennis court in an adult human.

AEC2 cells are responsible for the synthesis and secretion of surfactant, a complex lipid (fat) and protein mixture that reduces surface tension in the lungs and helps make the alveoli more stable. This material protects the alveoli from collapsing during exhalation. Premature babies often lack sufficient surfactant to breathe normally at birth.

Working in the laboratory, The Saban Research Institute team examined the cytokine (protein) profile in an injured AEC2 environment, theorizing that these molecules might promote surface cellular repair. They discovered that two major cytokines secreted by damaged AEC —CINC-2 and ICAM— were "chemoattractive" to AECs, meaning that these cytokines could attract other AEC to the site of damage to assist in repair. These protein molecules then expedited wound healing—a novel finding that Dr. Warburton calls "potentially highly significant because it could lead to new therapies."

In a related finding, the investigators also determined that the damaged AEC2 environment was chemoattractive to uncommitted human amniotic fluid stem cells (hAFSCs). Migration of the hAFSCs to the AEC2s increased 20-fold over normal, and the stem cells not only attached themselves within an in vitro AEC2 wound, they accelerated its healing.

"We are actively exploring the application of hAFSCs to enhance tissue repair in several organs, including the lung and the kidney," explained Dr. Warburton. "The finding that they respond positively to specific components of the alveolar milieu is highly encouraging."

Now the team plans to further analyze the entire set of proteins in both the healthy and diseased alveolar microenvironments to search out other proteins that may help reverse injury to the air sacs or speed their repair.