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DERT Papers of the Month

By Jerry Phelps
December 2006

Aldose Reductase Inhibition Fights Sepsis

Sepsis is characterized by an overreaction of the immune system in response to a severe bacterial infection. Death usually occurs from heart or other major organ failure. The incidence of sepsis is on the rise; a study conducted by the Centers for Disease Control and Prevention found that the number of cases has nearly tripled in the past couple of decades - from 82.7 cases/100,000 Americans in 1979 to 240.4 cases/100,000 in 2000. Much of the reason for this dramatic increase is attributed to antibiotic-resistant bacteria, caused by the overuse of antibiotics, and conditions resulting in a weakened immune system.

Now NIEHS-supported researchers at the University of Texas Medical Branch report that by blocking the activity of the enzyme aldose reductase in laboratory mice, they can prevent the development of sepsis and the resulting heart failure brought on from endotoxin exposure. The researchers blocked aldose reductase activity either through administration of sorbinil or small interfering RNA. Endotoxin administration caused large increases in serum and cardiac cytokines; this response was suppressed when aldose reductase activity was inhibited. Aldose reductase inhibition increased survival in mice following lethal doses of endotoxin.

Previous work by this team has shown that blocking aldose reductase reduced the inflammation-driven processes in colorectal cancer and diabetes. A compound very similar to sorbinil is now undergoing phase III clinical trials for use in diabetes.

Citation: Ramana KV, Willis MS, White MD, Horton JW, DiMaio JM, Srivastava D, Bhatnagar A, Srivastava SK. 2006. Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition. Circulation 114(17):1838-46.

Mutation Causes Some Cases of Brittle Bone Disease

Osteogenesis imperfecta (OI), also known as brittle bone disease, is a group of genetic bone disorders resulting in frequent fractures. A newly identified gene mutation helps explain a subset of cases of OI whose origin had until now remained mysterious. Brendan Lee at the Baylor College of Medicine and the Howard Hughes Medical Institute identified the mutation, which is responsible for up to 15 percent of OI cases. The mutation prevents collagen proteins from being properly modified after they are produced.

Using transgenic mice, Lee and his colleagues discovered that cartilage-associated protein (CRTAP) interacts with the enzyme responsible for the hydroxylation of the collagen protein. The mutation they discovered in CRTAP prevents this interaction and thus, prevents the protein modification resulting in damaged collagen and poor bone formation. The researchers reasoned that the same mutation might cause OI in humans. They focused on two families with a recessive form of OI that other researchers had mapped to the same chromosomal region containing the CRTAP gene. The research team found that a partial loss of CRTAP function caused OI and that a complete loss caused an even more severe form of the disease.

These findings could have important diagnostic implications. Until now, the only known genetic cause of OI was a structural mutation in type I collagen. According to Lee, this finding "adds a new dimension in terms of DNA testing." It also may also offer clues to the causes of connective tissue diseases that affect other parts of the body and gives insight into the basic mechanism of collagen formation.

Citation: Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, Castagnola P, Rauch F, Glorieux FH, Vranka J, Bachinger HP, Pace JM, Schwarze U, Byers PH, Weis M, Fernandes RJ, Eyre DR, Yao Z, Boyce BF, Lee B. 2006. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 127(2):291-304.

Link Between DNA Repair and DNA Remodeling Proteins

Two proteins involved in chromatin remodeling interact with nucleotide excision repair damage-recognition proteins to play a key role in enabling cells to repair DNA damage, according to a new study by NIEHS-grantee Michael Smerdon and colleagues at Washington State University. Their paper, published in Nature Structural and Molecular Biology was named "Article of the Month."

The researchers exposed yeast cells to UV radiation to cause DNA damage and then studied the actions of several DNA-associated proteins including eleven proteins in a complex called SWI/SNF. SWI/SNF changes the shape and arrangement of DNA with its associated structural proteins. They found that in yeast cells undergoing high rates of DNA repair, SWI/SNF is physically attached to two key proteins involved in recognizing DNA damage - Rad4 and Rad23. In yeast cells with the SWI/SNF complex knocked out, the cells lost the ability to remodel DNA and to repair DNA damage.

Each cell in the human body sustains thousands of DNA lesions each day as a result of normal metabolic activity, regardless of lifestyle choices such as smoking, UV exposure and diet. Smerdon and his group are continuing their work in human cells containing a SWI/SNF complex that appears to function similarly to the yeast complex. Smerdon is a Method to Extend Research In Time (MERIT) grant recipient from NIEHS; a prestigious grant award given to very few NIEHS grantees.

Citation: Gong F, Fahy D, Smerdon MJ. 2006. Rad4-Rad23 interaction with SWI/SNF links ATP-dependent chromatin remodeling with nucleotide excision repair. Nat Struct Mol Biol 13(10):902-7.

Subpollen Particles from Ragweed Pollen Contain Allegenic Proteins and Oxidases

Fragments of pollen grains, called subpollen particles (SPPs), are capable of reaching the lower regions of the lung and causing clinical symptoms associated with seasonal asthma, according to new research from NIEHS-supported researchers at the University of Texas Medical Branch in Galveston. How pollen allergens contribute to inflammation in the lower airways has been puzzling to researchers since only few pollen grains can reach the lower respiratory tract due to their size.

The researchers found that ragweed pollen grains release SPPs in the range of 0.5 to 4.5 microns in size. They determined that the SPPs contained allergenic proteins and possessed NADH or NADPH oxidase activity. Exposure of cultured cells to SPPs caused significant increases in the generation of reactive oxygen species and induced allergenic airway inflammation in laboratory mice. Pretreatment of the SPPs with NADH and NADPH oxidase inhibitors reduced their ability to increase reactive oxygen species in the airway epithelial cells and subsequently reduced airway inflammation.

These findings represent the first report showing allergenic proteins and oxidase activity by SPPs of respirable size produced by plants. The oxidase activity and the allergenic proteins work together to cause the development of severe allergic inflammation. The study provides insight into the role of SPPs in seasonal asthma and suggests that inhibitors of SPP oxidases may be useful therapeutic agents in reducing or preventing oxidative damage and inflammation.

Citation: Bacsi A, Choudhury BK, Dharajiya N, Sur S, Boldogh I. 2006. Subpollen particles: carriers of allergenic proteins and oxidases. J Allergy Clin Immunol 118(4):844-850.

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