Omar Tliba, DVM, PhD

Investigating Causes of Steroid-Resistant Asthma May Lead to New Treatments

Although most people with asthma respond to treatment with corticosteroids, these drugs don’t work in a substantial number of patients. Despite treatment with high doses of corticosteroids, these patients still have persistent lung inflammation and labored breathing, and are at increased risk of dying from asthma attacks.

Advances in understanding the mechanisms that are involved in the diminished action of corticosteroids will lead to the development of more effective therapy for patients who do not respond to steroids. In his American Lung Association-supported research, Dr. Tliba studied airway smooth muscle, a lung tissue that plays a key role in airway inflammation and bronchial hyper-responsiveness (airway “twitchiness”), two main features of asthma.

He hypothesized that chemical messengers called cytokines, which are released by immune cells in response to asthma triggers such as allergens and viruses, reduce the actions of corticosteroids in airway smooth muscle. Dr. Tliba discovered that a molecule called IRF-1 is involved in this process. His research suggests that increasing levels of IRF-1 may represent a novel therapeutic target for treating steroid-resistant asthma.

He then found that steroid resistance induced by protein chemical messengers called cytokines in airway smooth muscle could be reversed by vitamin D. The findings suggest that vitamin D also may exert some beneficial effects in the treatment of steroid-resistant proteins in patients with difficult-to-treat asthma. His research is likely to bring new insight into the development of novel therapeutic treatment of steroid-resistant asthma.

The American Lung association Biomedical Research Grant helped Dr. Tliba to apply for and receive a grant from the National Institutes of Health to study the mechanisms of inflammation-induced steroid resistance in asthma.

Damera G, Fogle HW, Lim P, Goncharova EA, Zhao H, Banerjee A, Tliba O, Krymskaya VP, Panettieri RA Jr. Vitamin D inhibits growth of human airway smooth muscle cells through growth factor-induced phosphorylation of retinoblastoma protein and checkpoint kinase 1. Br J Pharmacol. 2009 Nov; 158(6): 1429-41.

Bhandare R, Damera G, Banerjee A, Flammer JR, Keslacy S, Rogatsky I, Panettieri RA, Amrani Y, Tliba O. Glucocorticoid receptor interacting protein-1 restores glucocorticoid responsiveness in steroid-resistant airway structural ceils. Am J Respir Cell Mol Biol. 2010 Jan;42(l):9-15.

Goncharova EA, Goncharov DA, Damera G, Tliba O, Amrani Y, Panettieri RA Jr, Krymskaya VP. Signal transducer and activator of transcription 3 is required for abnormal proliferation and survival of TSC2-deficient cells: relevance to pulmonary lymphangioleiomyomatosis. Mol Pharmacol. 2009 Oct;76(4):766-77.

Bailey MT, Kierstein S, Sharma S, Spaits M, Kinsey SG, Tliba O, Amrani Y, Sheridan JF, Panettieri RA, Haczku A. Social stress enhances allergen-induced airway inflammation in mice and inhibits corticosteroid responsiveness of cytokine production. J Immunol. 2009 Jun 15;182(12):7888-96.

Clarke D, Camera G, Sukkar MB, Tliba O. Transcriptional regulation of cytokine function in airway smooth muscle cells. Pulm Pharmacol Ther. 2009 Oct;22(5):436-45.

Damera G, Tliba O, Panettieri RA Jr. Airway smooth muscle as an immunomodulatory cell. Pulm Pharmacol Ther. 2009 Oct;22(5):353-9.

Tliba O, Panettieri RA Jr. Noncontractile functions of airway smooth muscle cells in asthma. Annu Rev Physiol. 2009;71:509-35.

Tliba O. Panettieri RA Jr. Regulation of inflammation by airway smooth muscle. Curr Allergy Asthma Rep. 2008 May;8(3):262-8.

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(l):84-92.

Jain D, Keslacy S, Tliba O. Cao Y, Kierstein S, Amin K, Panettieri RA Jr, Haczku A, Amrani Y. Essential role of IFNbeta and CD38 in TNFalphainduced airway smooth muscle hyper-responsiveness. Immunobiology. 2008;213(6):499-509.

Tliba O. Amrani Y, Panettieri RA Jr. Is airway smooth muscle the “missing link” modulating airway inflammation in asthma? Chest. 2008 Jan;133(l):236-42.

Tliba O. Amrani Y. Airway smooth muscle cell as an inflammatory cell: lessons learned from interferon signaling pathways. Proc Am Thorac Soc. 2008 Jan 1;5(1):106-12.

Goncharova EA, Goncharov DA, Chisolm A, Spaits MS, Lim PN, Cesarone G, Khavin I, Tliba O, Amrani Y, Panettieri RA Jr, Krymskaya VP. Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation. Mol Pharmacol. 2008 Mar;73(3):778-88.

Tliba O, Damera G, Banerjee A, Gu S, Baidouri H, Keslacy S, Amrani Y. Cytokines induce an early steroid resistance in airway smooth muscle cells: novel role of interferon regulatory factor-1. Am J Respir Cell Mol Biol. 2008 Apr;38(4):463-72.