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DERT Papers of the Month

By Jerry Phelps
October 2006

Second Hand Smoke Injures Infants' Lungs

A new study by University of California Davis researchers details how the lungs of infants are damaged by secondhand cigarette smoke. NIEHS grantee Kent Pinkerton and colleagues exposed pregnant rhesus macaque monkeys to the same amount of smoke a woman would be exposed to if someone in her home or workplace smoked. Likewise, newborn monkeys were exposed to secondhand smoke levels equivalent to what a human baby would be exposed to if one of its parents or caregivers were a moderate to heavy smoker.

The research discovered that during pregnancy and the early postnatal period, critical times for lung development, secondhand smoke exposure caused premature death of alveolar cells due to apoptosis. Exposure to tobacco smoke was shown to suppress Nuclear Factor kappa Beta (NF-.B) activity and down-regulate NF-.B-dependent anti-apoptotic genes resulting in the increase of apoptotic death of alveolar cells in lung tissue.

Exposure in children to second hand smoke is a hazard and a widespread public health problem even though smoking continues to decline in the U.S. Exposure during the perinatal period causes adverse effects on lung development and reduces lung function. The current research conducted in this laboratory sheds light on the precise cellular mechanisms disrupted by environmental tobacco smoke and may elucidate new pathways for treating lung function decrements.

Presumably, killing cells at a higher rate during a critical developmental period when alveoli are supposed to be proliferating may have permanent effects on lung function. Pinkerton concludes that "smoke exposure causes significant damage and lasting consequences in newborns. The lungs may never be able to recover."

Citation: Zhong CY, Zhou YM, Joad JP, Pinkerton KE. 2006. Environmental tobacco smoke suppresses Nuclear Factor-{kappa}B signaling to increase apoptosis in infant monkey lungs. Am J Respir Crit Care Med 174(4):428-436.

Glutamate-Cysteine-Ligase Gene Polymorphisms Are Associated with Cystic Fibrosis Lung Disease

NIEHS-supported scientists report that a polymorphism in a gene that regulates glutathione synthesis influences the severity of cystic fibrosis lung disease. The research team examined the genetic makeup of 440 subjects with cystic fibrosis. They found that polymorphisms in the glutamate-cysteine ligase catalytic subunit gene were associated with lung function in subjects with a milder form of the defective gene that causes cystic fibrosis.

Cystic fibrosis is a genetic disease affecting approximately 30,000 children and adults in the United States. A defective gene, known as the cystic fibrosis trans-membrane conductance regulator causes the body to produce abnormally thick, sticky mucus that clogs the lungs and can lead to life-threatening lung infections. Every year about 1000 people are diagnosed with the disease in the U.S. Life expectancy is generally shorter for people with the disease although medical advancements have prolonged life for many.

This finding demonstrates that lung disease severity in people with cystic fibrosis is mediated by factors that regulate levels of glutathione in the lung. The authors conclude that treatments to increase lung levels of glutathione may reduce the decline in lung function seen in patients with cystic fibrosis, especially those with the milder form of the mutation.

Citation: McKone EF, Shao J, Frangolias DD, Keener CL, Shephard CA, Farin FM, Tonelli MR, Pare PD, Sandford AJ, Aitken ML, Kavanagh TJ. 2006. Variants in the glutamate-cysteine-ligase gene are associated with cystic fibrosis lung disease. Am J Respir Crit Care Med 174(4):415-419.

αSynuclein Gene Promoter Variability and Parkinson's Disease

Variability in the α-synuclein (SNCA) gene promoter is linked with a greater susceptibility for Parkinson's disease, according to a study in the August 9 issue of the Journal of the American Medical Association. Previous research has shown that the origins of Parkinson's can be both genetic and environmental. One of the most promising leads in the genetics of Parkinson's disease is the potential role of the SNCA gene. Some evidence suggests that may be associated with risk of Parkinson's disease, but studies from different populations have yielded conflicting results. Large-scale studies have been lacking.

NIEHS grantees Demetrius M. Maraganore and Harvey Checkoway and colleagues with the Genetic Epidemiology of Parkinson's Disease Consortium, conducted a study to examine several issues, including whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene is associated with Parkinson's disease susceptibility. The researchers performed a collaborative analysis of individual-level data on SNCA REP1 and markers in patients with Parkinson's disease and controls. Eleven participating sites in the genetics consortium provided clinical data for 2,692 cases and 2,652 controls. The researchers found that genotypes defined by the 263 base-pair gene were associated with Parkinson's disease.

"Our study demonstrates that the SNCA gene is not only a rare cause of autosomal dominant Parkinson disease in some families, but also a susceptibility gene for Parkinson disease at the population level. Based on our results, we estimate that REP1 locus variability may explain approximately 3 percent of the risk in the general population. This is in the same range as the population effect of other common variants implicated in Parkinson disease. The additive effects of these and other common gene variants may ultimately account for a substantial fraction of the susceptibility to Parkinson disease," the authors write.

Citation: Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R et al. 2006. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 296(6):661-670.

Inflammatory Enzyme Affects Motor Neuron Damage in Amyotrophic Lateral Sclerosis

Serge Przedborski of Columbia University reported in the August 8 edition of the Proceedings of the National Academy of Sciences new insights into the death of motor neurons resulting from amyotrophic lateral sclerosis (ALS). Przedborski has been a pioneer in the investigation of the molecular mechanisms leading to the death of neurons that occurs in ALS and Parkinson's disease.

Also called Lou Gehrig's disease for the legendary New York Yankee first baseman who died of the disease in 1941, ALS is a progressive neuromuscular disease that weakens and eventually destroys motor neurons connecting the brain with the skeletal muscles. Patients gradually lose the ability to speak, swallow and move voluntarily. Sensory function and intellectual ability are unaffected, and death usually results from loss of respiratory function. Approximately 30,000 patients in the United States currently have ALS. The disease has no racial, socioeconomic or ethnic boundaries. The life expectancy of ALS patients is usually three to five years after diagnosis. ALS is most commonly diagnosed in middle age and affects men more often than women.

The researchers discovered that an enzyme known as reduced-form nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an important component in the generation of destructive reactive oxygen species during inflammation, is active in the spinal cords of ALS patients and also in a mouse model of the disease. When the researchers inactivated the enzyme in the mice, neurodegeneration was significantly delayed and the mice lived longer. Additional studies also showed that NADPH-oxidase-derived oxidative products also damaged proteins including insulin-like growth factor 1 (IGF1) receptors located on motor neurons. IGF1 has been demonstrated to have therapeutic potential in ALS patients. These results suggest that co-administration of an anti-inflammatory agent may improve the therapeutic response of IGF1 in ALS patients.

Citation: Wu DC, Re DB, Nagai M, Ischiropoulos H, Przedborski S. 2006. The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc Natl Acad Sci U S 103(32):12132-12137.

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