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DIR Papers of the Month

By Eddy Ball
June 2007

Defects in mtDNA Replication Linked to Cardiac Dysfunction

In a study funded in part by NIEHS, researchers in the Laboratory of Molecular Genetics collaborated with investigators at the Emory University School of Medicine and the National Jewish Medical Center to study effects of mutant polymerase gamma (Polγ) on organ dysfunction and premature death. They evaluated the effects of the mutation on oxidative stress and cardiac parameters in four lines of transgenic (TG) mice with wild type (WT) mice as controls.

The researchers used TG mice generated with a cardiac-targeted human mutant of the gene, POLG, that encodes Y955C Polγ, resulting in stalling in mitochondrial DNA (mtDNA) synthesis. This mutation produced interference in mtDNA replication, oxidative stress, cardiac dysfunction and premature death - as early as 90 days post partum in the most severely affected TG line (D) as compared to an average of more than 600 days in WT animals. Examination of hemi-sections of thorax in TG line (D) animals, terminated at 21 days, showed massive enlargement of the heart with bilateral atrial enlargement consistent with congestive heart failure.

This study design overcame an important deficit of earlier studies by experimenting with a Polγ mutation that had a pathophysiologically based counterpart in human disease - with findings that "forge a pathogenetic link between defective mtDNA replication and cardiac dysfunction."

Citation: Lewis W, Day BJ, Kohler JJ, Hosseini SH, Chan SS, Green EC, Haase CP, Keebaugh ES, Long R, Ludaway T, Russ R, Steltzer J, Tioleco N, Santoianni R, Copeland WC( Exit NIEHS. 2007. Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma. Lab Invest 87(4):326-335.

Advances in Detection of Pre-Invasive Lung Cancer in LIFE Study

Investigators in the NIEHS-funded Light Induced Fluorescence Endoscopy (LIFE) project have reported on enhanced detection of pre-invasive lesions using fluorescent bronchoscopy and on improvements to molecular analysis using laser capture microdissection (LCM) of frozen biopsy specimens.

Investigators from NIEHS collaborated with UNC Medical Center researchers in the six-year LIFE study of 47 high risk patients with a history of lung or upper respiratory cancer or who were current or former smokers with at least a 15 pack-year history. The patients underwent bronchoscopy at the time of enrollment in 1999, and 22 underwent follow-up bronchoscopies. During the study, researchers collected 390 snap-frozen biopsies from 106 bronchoscopic procedures - producing a total of almost 4,000 diagnostic slides.

Researchers confirmed the superior detection rate of the fluorescence technology and its ability to localize lesions as small as 0.5 mm, about one-tenth the size of the smallest identified by white light. They also determined that "snap-freezing [of biopsy specimens] was optimal for molecular studies since it avoided the cross-linking induced by formalin fixation" and preserved "the morphologic features of the bronchial mucosa." In addition, LCM produced "virtually pure epithelial cell populations" from bronchial biopsies, aiding in the search for molecular biomarkers of the disease at its most treatable stage.

Citation: Flake GP, Rivera MP, Funkhouser WK, Maygarden SJ, Meadows KL, Long EH, Stockton PS, Jones TC, Yim HW, Slebos RJ, Taylor JA( Exit NIEHS. 2007. Detection of pre-invasive lung cancer: technical aspects of the LIFE project. Toxicol Pathol 35(1):65-74.

Role of Retinoid-Related Orphan Receptor γ in Inflammatory Disease

Researchers in the NIEHS Laboratories of Respiratory Biology and Experimental Pathology collaborated with UNC scientists to describe control by Retinoid-Related Orphan Receptor gamma (RORγ) of antigen-induced inflammation in animals. Their study was funded jointly by NIEHS intramural and NIH extramural grants.

The investigators studied the responses of RORγ deficient mice and their wild type (WT) littermates to chicken ovalbumin to induce allergic inflammation. Following an exposure regimen over a 19-day period, the researchers evaluated lung lavage fluid and lung sections for inflammatory, eosinophils and lymphocytes, immunoglobulins and other markers of the adaptive immune response.

They reported "unexpected increases" in tumor necrosis factor-α, interleukin (IL)-2, and interferonγ along with reciprocal reductions in IL-4, IL-5 and IL-13 - possibly the result of several mechanisms working in concert. The results indicated that cytokine profiles were altered and allergic lung inflammation profoundly blunted in RORγ-deficient mice, as compared to WT mice. These observations suggest that activation of RORγ augments the inflammatory response.

The results of the study add significantly to the understanding of the contribution of this member of the ROR subfamily in controlling the adaptive immune response. The authors called for "further studies of the role of ROR in immune cell function and host defense determine whether ROR antagonists could provide useful therapeutic strategies for asthma and other inflammatory disease."

Citation: Tilley SL, Jaradat M, Stapleton C, Dixon D, Hua X, Erikson CJ, McCaskill JG, Chason KD, Liao G, Jania L, Koller BH, Jetten AM( Exit NIEHS. 2007. Retinoid-related orphan receptor gamma controls immunoglobulin production and Th1/Th2 cytokine balance in the adaptive immune response to allergen. J Immunol 178(5): 3208-3218.

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