Alveolar cell apoptosis is involved in the pathogenesis of emphysema, a prevalent disease primarily caused by cigarette smoking. We report that ceramide, a second messenger lipid, is a critical mediator of alveolar destruction in emphysema. Inhibition of enzymes controlling de novo ceramide synthesis prevented alveolar cell apoptosis, oxidative stress and emphysema caused by blockade of the VEGF receptors in both rats and mice. Emphysema was reproduced with intra-tracheal instillation of ceramide in naïve mice. A feed-forward mechanism of ceramide synthesis due secretory acid sphingomyelinase was supported by the neutralizing effects of ceramide-specific antibody in mice and by sphingomyelinase-deficient fibroblasts. Stimulation of sphingosine-1-phosphate signaling prevented lung apoptosis, implicating that ceramide to sphingosine-1-phosphate balance is required for maintenance of alveolar septal integrity. Finally, increased lung ceramides in patients with smoking-induced emphysema position ceramide upregulation as a critical pathogenetic element and a promising target in this disease lacking effective therapies.

Abstract-Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lep ob mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl-coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity. Key Words: obstructive sleep apnea Ⅲ cholesterol homeostasis Ⅲ lipids Ⅲ hypoxia Ⅲ mouse Ⅲ gene expression O bstructive sleep apnea (SA) is the most common form of sleep-disordered breathing and is characterized by recurrent collapse of the upper airway during sleep, leading to periods of intermittent hypoxia (IH) and sleep fragmentation. 1 SA is present in 2% of women and 4% of men in the general US population, but it is more common in obese individuals. 2,3 SA is an independent risk factor for increased cardiovascular morbidity and mortality. 4 -7 It has been postulated that metabolic dysfunction in SA may provide an intermediate step linking IH and sleep disturbances to cardiovascular disease. Although several recent studies have focused on the effects of SA on dysregulating glucose and insulin metabolism, 2,8 -10 little information is available about the impact of SA on lipid metabolism. Abnormalities in lipid regulation that occur in response to SA may act to increase the cardiovascular risk in an already susceptible population. Although obesity is one of the risk factors for elevations in total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels, 11 recent clinical studies indicate that SA may also contribute to hypercholesterolemia. [12][13][14][15] Thus, obesity and IH may interact to alter lipid metabolism in SA.Key steps of lipid metaboli...

These observations suggest that in glaucoma, retina and optic nerve head microglia activation may be a factor in the early decline in function of the optic nerve and its subsequent degeneration.