Vitamin D may slow the progressive decline in the ability to breathe that can occur in people with asthma as a result of human airway smooth muscle (HASM) proliferation, according to researchers at the University of Pennsylvania.
The group found that calcitriol, a form of vitamin D, naturally synthesized within the body, reduced growth-factor-induced HASM proliferation in cells isolated from both persons with asthma and from persons without the disease. The proliferation is a part of process called airway remodeling, which occurs in many people with asthma, and leads to reduced lung function over time.
The researchers believe that by slowing airway remodeling, they can prevent or forestall the irreversible decline in breathing that leaves many asthmatics even more vulnerable when they suffer an asthma attack.
“Calcitriol has recently earned prominence for its anti-inflammatory effects,” said Gautam Damera, Ph.D., who will present the research at the American Thoracic Society’s 105th International Conference in San Diego on Wednesday, May 20. “But our study is the first to reveal the potent role of calcitriol in inhibiting ASM proliferation.”
The experiments were conducted with cells from 12 subjects, and the researchers compared calcitriol with dexmethasone, a corticosteroid prescribed widely for the treatment of asthma. Although, dexmethasone is also a powerful anti-inflammatory agent, the researchers found that it had little effect on HASM growth.
Dr. Damera and his colleagues found calcitriol inhibits HASM in a dose-dependent manner, with a maximum inhibitory effect of 60 percent ± 3 percent at 100nM.
As part of the University of Pennsylvania’s Airway Biology Initiative, the researchers are planning a randomized control trial of calcitriol in patients with severe asthma and expect to have data from the trial in about a year’s time.
With its anti-inflammatory qualities and its ability to inhibit smooth muscle proliferation, Dr. Damera said, calcitriol may become an important new therapy, used alone or in combination with already prescribed steroids, for treating steroid-resistant asthma.
Dr. Damera and his colleagues have also conducted experiments to determine the mechanism by which calcitriol retards HASM proliferation. They believe the vitamin works by inhibiting activation of distinct set of proteins responsible for cell-cycle progression.
The investigators have also conducted experiments to determine whether calcitriol, which is currently used to treat psoriasis, could be an effective therapy for COPD. Although preliminary, their data shows that calcitriol appears to reduce pro-inflammatory cytokine secretions in COPD. As with asthma, the researchers believe, calcitriol may also have the added benefit of slowing, if not stopping, the progression of airway remodeling. Others in the field believe calcitriol may also have the potential to inhibit the development and growth of several types of cancer.
BACKGROUND AND PURPOSE: Chemokines play a critical role in the pathogenesis of asthma and facilitate the recruitment of inflammatory cells in the airways. Evidence now suggests that airway smooth muscle (ASM) may serve as a source of chemokines in inflamed airways. Although vitamin D has potent anti-inflammatory properties in vitro in some cell types, its effects on ASM cells remain unclear. Here, we investigated whether 1alpha, 25-dihydroxy vitamin D3 (calcitriol) modulated chemokine production in ASM. EXPERIMENTAL APPROACH: Human ASM cell cultures were derived from tracheal samples taken during surgery. ASM cells were treated with tumour necrosis factor alpha (TNFalpha) and/or interferon gamma (IFNgamma) for 24 h in the presence of calcitriol and/or the glucocorticoid fluticasone added 2 h before. RANTES (regulated upon activation, normal T-cell expressed and secreted), interferon-inducible protein 10 (IP-10) and fractalkine (FKN) levels in cell supernatants were measured by ELISA. KEY RESULTS: In TNFalpha-treated cells, calcitriol inhibited RANTES and IP-10 secretion in a concentration-dependent manner. FKN levels were negligible. In TNFalpha/IFNgamma-treated cells, whereas fluticasone or calcitriol alone partially inhibited RANTES secretion (by 38 and 20%, respectively), the combination of both drugs additively inhibited RANTES secretion (by 60%). No effect was observed on IP-10 secretion. Whereas fluticasone enhanced FKN secretion (by 50%), calcitriol significantly decreased FKN levels (by 50%). Interestingly, calcitriol blocked the stimulatory effect of fluticasone on FKN secretion, which was inhibited by 60% with the combination of calcitriol and fluticasone. CONCLUSIONS AND IMPLICATIONS: These findings suggest that vitamin D uniquely modulates human ASM expression of chemokines and may exert some beneficial effects in the treatment of steroid-resistant patients with asthma.
Banerjee A, Damera G, Bhandare R, Gu S, Lopez-Boado Y, Panettieri R Jr, Tliba O. Vitamin D and glucocorticoids differentially modulate chemokine expression in human airway smooth muscle cells. Br J Pharmacol. 2008 Sep;155(1):84-92. Epub 2008 Jun 16.
American Thoracic Society (ATS) Released: Tue 12-May-2009