Smoking and Thyroid-Associated Ophthalmopathy: A Novel Explanation of the Biological Link

Introduction: Cigarette smoking is the strongest modifiable risk factor for developing thyroid-associated ophthalmopathy (TAO), and the severity of TAO is related to the current number of cigarettes smoked per day. We aimed to establish the effects of cigarette smoke extract (CSE) on an in vitro model of TAO. Methods: Orbital tissue was taken during surgery from 10 patients with TAO and nine control subjects. Orbital fibroblasts were cultured and exposed to CSE, and intercellular adhesion molecule 1 (ICAM1) expression was measured by flow cytometry. Glycosaminoglycan production was measured by hyaluronic acid ELISA. Orbital fibroblasts were grown in adipogenic media with or without CSE and/or IL-1, and the degree of adipogenesis was quantified. Results: Fibroblasts from patients with TAO and controls showed similar responses. ICAM1 expression was not affected by CSE. Hyaluronic acid production was stimulated by CSE in a dose-dependent manner (correlation coefficient, 0.978; P = 0.022), with 5% CSE causing an increase of 44% (P = 0.001). CSE increased adipogenesis in a dose-related manner, as did IL-1. The effects of CSE and IL-1 on adipogenesis were synergistic, with the degree of adipogenesis in the well containing both 5% CSE and 0.1 ng/ml IL-1 being double the magnitude of the sum of the values obtained from either stimulus alone (P < 0.001). Addition of an anti-IL-1 antibody to the well containing both 5% CSE and 0.1 ng/ml IL-1 reduced the degree of adipogenesis by 82% (P < 0.001). Conclusion: These findings may help explain how cigarette smoking has a detrimental effect in TAO and suggests that IL-1 may be an attractive therapeutic target in TAO.