An invasion of fibroblasts stimulated by the naturally occurring protein interleukin-13 (IL-13) is partially responsible for changes that occur in the airways of asthma patients, according to researchers at Duke University.
The paper “LL Leptin Modulates the Expression Of Procollagen 1± In Airway Fibroblasts In Asthma” was published online in the American Journal of Respiratory and Critical Care Medicine. The study is the latest effort by researchers to better understand the processes involved in airway remodeling that can cause breathing difficulties in patients with asthma.
The Duke team enrolled 37 subjects including 20 men and women with mild asthma who were not taking inhaled corticosteroids and 17 healthy controls. All asthmatic subjects were diagnosed with asthma for at least one year prior to study enrollment. Airway cells were collected from all patients using bronchoscopy. After application of IL-13, invading cells were counted using microscopy.
While no significant difference in airway fibroblast invasion was observed between asthmatic subjects and controls, the addition of IL-13 resulted in a significant increase in airway fibroblast invasion in asthma patients as compared to normal controls, the study found. Airway fibroblasts of asthmatic subjects invaded in greater numbers than those of control subjects.
"We show for the first time that airway fibroblasts, isolated directly from patients with asthma and stimulated with IL-13, invade in significantly greater numbers than those isolated from normal control subjects," says Jennifer Ingram, Ph.D., assistant research professor of medicine at Duke University.
"In this novel mechanism of airway remodeling in asthma patients, IL-13 acts in combination with other mediators produced by cells in the airways: transforming growth factor-β1 (TGF-β1), which causes cellular changes, and matrix metalloproteinases (MMPs), which act to break down proteins," Dr. Ingram adds. "Together, these agents cause cellular changes that lead to loss of lung function in asthma patients."
During airway remodeling, many of the fibroblast responses that occur are comparable to the interaction between cancer cells and connective tissue cells called stromal fibroblasts. Studies have shown these fibroblasts actively produce pro-invasive factors that result in metastasis. Fibroblast production of TGF-β1 has been implicated as a key pro-invasive factor in colon, breast, and squamous carcinomas. IL-13, a critical regulator of the allergic response, has been implicated in cellular invasion in cancer and rheumatoid arthritis.
"The invasion of fibroblasts into the airway in asthmatic patients is one of several key features of airway remodeling," Dr. Ingram states. "In a normal response, fibroblasts begin wound healing by depositing proteins and interacting with inflammatory cells. In asthma, this wound healing and remodeling response in the airway becomes deranged and uncontrolled, leading to increased numbers of fibroblasts invading the airway and contributing to fibrosis with diminished lung function over time."
The study focused on the effect of IL-13 in patients with mild asthma. Future studies should explore whether fibroblasts in severe asthmatics are more invasive, Dr. Ingram says.
"In addition, goals of future studies should focus on specific MMPs that are involved in remodeling as well as characterization of the gene profiles of invading fibroblasts in order to further define this feature of airway remodeling," she adds. "Development of therapies specifically targeting IL-13 may play a key role in preventing airway remodeling in asthma."