Pathology of the olfactory epithelium: smoking and ethanol exposure.

OBJECTIVE: To investigate the effects of tobacco smoke on the olfactory epithelium. Cigarette smoking has been associated with hyposmia; however, the pathophysiology is poorly understood. The sense of smell is mediated by olfactory sensory neurons (OSNs) exposed to the nasal airway, rendering them vulnerable to environmental injury and death. As a consequence, a baseline level of apoptotic OSN death has been demonstrated even in the absence of obvious disease. Dead OSNs are replaced by the mitosis and maturation of progenitors to maintain sufficient numbers of neurons into adult life. Disruption of this balance has been suggested as a common cause for clinical smell loss. This current study will evaluate the effects of tobacco smoke on the olfactory mucosa, with emphasis on changes in the degree of OSN apoptosis. STUDY DESIGN: A rat model was used to assess the olfactory epithelium after exposure to tobacco smoke. METHODS: Rats were exposed to tobacco smoke alone (for 12 weeks), smoke plus dietary ethanol (for the final 5 weeks), or to neither (control). Immunohistochemical analysis of the olfactory epithelium was performed using an antibody to the active form of caspase-3. Positive staining for this form of the caspase-3 enzyme indicates a cell undergoing apoptotic proteolysis. RESULTS: Control rats demonstrated a low baseline level of caspase-3 activity in the olfactory epithelium. In contrast, tobacco smoke exposure triggered a dramatic increase in the degree of OSN apoptosis that affected all stages of the neuronal lineage. CONCLUSIONS: These results support the following hypothesis: smell loss in smokers is triggered by increased OSN death, which eventually overwhelms the regenerative capacity of the epithelium.

Pneumolysin-induced complement depletion during experimental pneumococcal bacteremia.

To quantify complement depletion by pneumolysin during Streptococcus pneumoniae bacteremia, cirrhotic and control rats were infected intravenously with one of three isogenic mutant strains of S. pneumoniae expressing different forms of pneumolysin. Outcome measures included clearance of the organisms from the bloodstream, alterations in 50% serum hemolytic complement (CH(50)) activity and complement C3 levels during infection, and serum opsonic capacity at 18 h postinfection. Cirrhotic rats had significantly lower CH(50) and C3 levels than control rats, both before and after infection. However, initial complement levels did not predict bacterial load after 18 h of infection. Changes in CH(50) and C3 levels over the 18-h period correlated with numbers of H+C+ but not H+C- or PLY- organisms in the bloodstream at 18 h postinfection. The sera of cirrhotic rats infected with the H+C+ strain had significantly decreased levels of C3 and showed significantly lower opsonizing activity for S. pneumoniae than sera from H+C+-infected control rats. These studies suggest that under limiting concentrations of complement, the expression of pneumolysin by pneumococci has a significant, negative effect on serum complement levels and reduces serum opsonic activity.

Use of rat models to mimic alterations in iron homeostasis during human alcohol abuse and cirrhosis.

With alcoholism, there are marked disturbances in iron homeostasis that are linked to alterations in serum transferrin and ferritin concentrations. This study identifies rat models of alcohol abuse that closely mimic these disturbances. Male rats were placed in one of the following three protocols: (1) pair-feeding of liquid diets for 1-8 weeks; (2) agar-block feeding for 8 weeks; or (3) generation of cirrhosis with CCl(4). Serum samples were analyzed for ferritin, transferrin, and iron levels, and the transferrin iron saturation and ferritin/transferrin ratios were calculated. Liver iron concentrations were also determined. Serum transferrin levels were elevated in animals fed alcohol for 8 weeks in pair-feeding and agar-block feeding protocols, but reduced in rats with cirrhosis. Serum ferritin concentration was reduced in rats fed ethanol in the liquid diet, but increased in rats consuming ethanol in agar blocks, in rats pair-fed the liquid control diet, and in rats with cirrhosis. This finding was mirrored by liver nonheme iron concentrations in all experimental groups, but not in the corresponding control groups. Serum iron levels were significantly elevated only in rats fed the liquid control diet. There was a progressive decrease in transferrin iron saturation and ferritin/transferrin ratios for animals fed ethanol in the liquid diet, but not when ethanol was ingested from agar blocks. The development of cirrhosis resulted in elevated liver iron concentrations and doubled ferritin/transferrin ratios. It is concluded that these models may be used to study disturbances in iron homeostasis that occur during alcohol abuse and the (subsequent) development of liver disease.