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Intramural Papers of the Month

By Eddy Ball and Lillian Gu
August 2007

Inhibiting Enzyme Reduces Fluid in the Lung Caused by Viral Infection

A team of researchers in the NIEHS Laboratory of Respiratory Biology has demonstrated that pharmacological inhibition of key enzymes in lung membrane can significantly reduce the accumulation of fluid in lung tissue infected by respiratory syncytial virus (RSV). Their study, published online in June, elicits for the first time the mechanisms by which this most common cause of respiratory tract viral infection increases lung membrane permeability, leading to the accumulation of fluid in infected lungs — a characteristic feature of viral hemorrhagic diseases.

The investigators performed in vitro experiments on lung membrane epithelial cells and demonstrated how RSV infection caused a decrease in the membrane’s ability to resist the transfer of fluid into the lung. They also showed that inhibition of the kinase p38 MAPK (and, to a lesser extent, of JNK and ERK) can effectively reduce RSV-induced gap formation.

The findings are significant because they represent an important breakthrough in understanding the mechanism by which RSV activates enzyme pathways and a heat shock protein, Hsp27, and causes other physiological changes that lead to membrane permeability. By triggering fluid accumulation in the lung, RSV can set the stage for secondary bacterial inflections and even life-threatening pneumonia among infants, immune-compromised patients and the elderly.

Citation: Singh D, McCann KL, Imani F (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17557802&ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) Exit NIEHS Website. 2007. MAPK and Hsp27 Activation Are Associated With RSV Induction of Human Bronchial Epithelial Monolayer Disruption. Am J Physiol Lung Cell Mol Physiol. Doi:10.1152ajplung.00097.2007

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COX-2 Inhibits UVB-Induced Epidermal Apoptosis after Acute Exposure

In collaboration with a scientist from the University of Texas, researchers in the NIEHS Laboratory of Molecular Carcinogenesis reported the effects of ultraviolet light B (UVB) on mice deficient in cyclooxygenases 1 and 2 (COX-1 and COX-2) in a study published in the May issue of the journal Molecular Carcinogenesis. Chronic UVB exposure has been implicated as a major cause of skin cancer, which is in part attributed to an increase in prostaglandin (PG) production due to the induction of COX-2.

While previous studies have used non-steroidal anti-inflammatory drugs (NSAIDs) to inhibit COX activity, the present study used COX-deficient mice to reduce PG production and avoid any COX-independent effects that NSAIDs may have.

The investigators found that COX-2, but not COX-1, deficient mice displayed increased UVB-induced epidermal apoptosis, or programmed cell death, and impaired epidermal recovery. Thus, COX-2 induction appeared to offer immediate benefits by protecting against the acute effects of UVB exposure in the mouse epidermis. However, the researchers concluded that while COX-2 protects against the early effects of UVB exposure, it can contribute to tumor formation during chronic UVB exposure.

Citation: Akunda JK, Chun KS, Sessoms AR, Lao HC, Fischer SM, Langenbach R (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17238138&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) Exit NIEHS Website. 2007. Cyclooxygenase-2 deficiency increases epidermal apoptosis and impairs recovery following acute UVB exposure. Mol Carcinog 46(5):354-362.

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Dairy Products and Parkinson’s Disease

A team of researchers led by an investigator in the NIEHS Epidemiology Branch reported findings of an association between high intake of dairy products and increased risk for developing Parkinson’s Disease (PD), particularly among men. The study, which appeared in the May issue of the American Journal of Epidemiology, was funded by grants from NIH, NIEHS, the Kinetics Foundation and the Michael J. Fox Foundation for Parkinson’s Research.

The team prospectively investigated 57,689 men and 73,175 women who were enrolled in the American Cancer Society’s Cancer Prevention Study II nutritional cohort in 1992-1993 and completed follow-up surveys in 1997, 1999 and 2001. Of that cohort, the investigators had diagnostic confirmation for 388 cases of incident PD. Relative risk of PD was calculated by statistical analysis of baseline intakes of nutrients from dairy products or other sources.

The team found that men who were in the highest 20% of milk consumption had approximately 80% higher risk of PD as compared with men in the lowest 20%. The association was weaker in women. As demonstrated in a meta-analysis of pooled data, the study confirmed the findings of earlier large-scale prospective studies, the Health Professionals Follow-up Study, Nurses’ Health Study and the Honolulu-Asia Aging Study.

Citation: Chen H, O'Reilly E, McCullough ML, Rodriguez C, Schwarzschild MA, Calle EE, Thun MJ, Ascherio A (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17272289&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) Exit NIEHS Website. 2007. Consumption of dairy products and risk of Parkinson's disease. Am J Epidemiol 165(9):998-1006.

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Genetic Polymorphisms, Childhood Asthma and Atopy

In an NIEHS-funded study, an international team of researchers reported a link between genetic polymorphism in the transforming growth factor beta-1 gene (TGFB1) and childhood asthma and atopy. After genotyping 546 asthmatic children and their parents in Mexico, the investigators pinpointed three out of the five single nucleotide polymorphisms (SNPs) in TGFB1 they tested to be important — the T allele of C-509T, the C allele of T869C and the C allele of rs7258445.

Expressed in many inflammatory cells including airway epithelial cells, TGFB1 is a cytokine, a protein signaling compound. TGFB1 is found in higher levels in the lung fluid of asthma patients and has been hypothesized to be involved in allergic inflammation and airway constriction.

The five TGFB1 SNPs, selected based on functional and linkage disequilibrium data, were genotyped from blood samples. Atopy, or the genetic tendency to develop allergic reactions, was measured via a skin prick test with a battery of 24 aeroallergens. Statistical analysis correlated atopy data, asthma data and the SNP data to identify three relevant SNPs.

This study is the largest of its kind and the first to report a connection between SNP rs7258445 and asthma or atopy, adding significantly to evidence for a role of TGFB1 variations in asthma and atopy.

Citation: Li H, Romieu I, Wu H, Sienra-Monge JJ, Ramirez-Aguilar M, Del Rio-Navarro BE, Del Lara-Sanchez IC, Kistner EO, Gjessing HK, London SJ (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17333284&ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) Exit NIEHS Website. 2007. Genetic polymorphisms in transforming growth factor beta-1 (TGFB1) and childhood asthma and atopy. Hum Genet 121(5):529-538.


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