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BackgroundRetinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines which participate in clearing viral infections. Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections.MethodsWe generated a RIG-I transgenic (TG) mouse strain that expresses the RIG-I gene product under the control of the human lung specific surfactant protein C promoter. We compared the mortality and host immune responses of RIG-I TG mice and their litter-matched wild type (WT) mice following challenge with influenza A virus (IAV).ResultsRIG-I overexpression increased survival of IAV-infected mice. CS exposure increased mortality in WT mice infected with IAV. Remarkably, the effect of RIG-I overexpression on survival during IAV infection was enhanced in CS-exposed animals. CS-exposed IAV-infected WT mice had a suppressed innate response profile in the lung compared to sham-exposed IAV-infected WT mice in terms of the protein concentration, total cell count and inflammatory cell composition in the bronchoalveolar lavage fluid. RIG-I overexpression restored the innate immune response in CS-exposed mice to that seen in sham-exposed WT mice during IAV infection, and is likely responsible for enhanced survival in RIG-I TG mice as restoration preceded death of the animals.ConclusionsOur results demonstrate that RIG-I overexpression in mice is protective for CS enhanced susceptibility of smokers to influenza infection, and that CS mediated RIG-I suppression may be partially responsible for the increased morbidity and mortality of the mice exposed to IAV. Thus, optimizing the RIG-I response may be an important treatment strategy for CS-enhanced lung infections, particularly those due to IAV.

Primary neuroendocrine tumors of the larynx are rare, with moderately differentiated neuroendocrine carcinoma (MDNC) being the most frequent histologic type. We report a MDNC in a 57-year-old gentleman with an enlarging right-sided neck mass. Flexible fiberoptic exam revealed a right arytenoid lesion. Histology from excisional biopsy was concerning for medullary thyroid carcinoma (MTC) versus NET of the larynx. Immunohistochemistry was diffusely positive for calcitonin and CEA and focally positive for TTF-1. Serum calcitonin was elevated. Thyroid ultrasound was unremarkable. The patient underwent laryngectomy, thyroidectomy, and neck dissection. Pathology showed neuroendocrine carcinoma of right arytenoid with positive cervical lymph nodes. A 4 mm deposit of NET was present in right thyroid with adjacent intravascular tumor consistent with thyroidal metastasis from a primary laryngeal NET (MDNC). MDNC and MTC can be microscopically indistinguishable. Both tumors can stain positively for calcitonin and CEA. TTF-1 staining has been useful to help distinguish these tumors as it is strongly and diffusely positive in MTC, but usually negative (or only focally positive) in MDNC. We report the fourth case of primary neuroendocrine carcinoma of the larynx associated with elevated serum calcitonin level and the first such case associated with metastasis to the thyroid.