Publications

Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(-/-) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(-/-) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy.

Standard methods to monitor tuberculosis (TB) treatment response rely on sputum microscopy and culture conversion. Alternatives to these methods are needed for those patients whose sputum tests are smear or culture negative. Here, we examine anti-phospholipid IgM antibody level changes as a biomarker for treatment response in smear positive TB patients. Serum samples were obtained from 40 pulmonary TB patients at the start and end of the intensive phase treatment (IPT) from the CDC-TB Trials Consortium randomized clinical trial in Kampala, Uganda. Samples were screened by ELISA for IgM levels against five phospholipids found in Mycobacterium tuberculosis and host cells. Lipid antigens included cardiolipin (CL), phosphatidyl inositol (PI), phosphatidyl ethanolamine (PE), phosphatidyl choline (PTC), and sphingolipid (SL). Levels of IgM against all phospholipids significantly decreased (p = 0.034, 0.001, 0.008 0.008, 0.040, respectively) following anti-TB drug treatment in patients without lung cavitary disease at baseline. The mean sensitivity of this test in these patients was 83% when the IgM response to a single lipid antigen was used; it was >90% when responses to 2 or more lipids were assessed. In contrast, cavitary TB patients showed an overall IgM increase, with a significant rise against PE (p = 0.025). There was no significant difference in the change in antibody levels between patients who remained culture-positive and those who culture-converted after 40 doses of drug therapy. The measurement of IgM anti-phospholipid antibodies may be a useful biomarker to monitor treatment response in non-cavitary TB patients.

African American youth bear a disproportionate burden of sexually transmitted infections. Environmental stressors may lead to increased hopelessness, which in turn can lead to increases in risk-taking behavior. This study explored the hypothesis that as hopelessness increases, sexual risk behavior will increase-specifically, inconsistent condom use and increased number of sex partners. In 2010, 108 African American men 15 to 24 years old responded to sexual behavior questions and Beck's Hopelessness Scale. The associations between hopelessness and sexual risk behaviors were evaluated with multivariate logistic regression. Increased hopelessness was associated with increased inconsistent condom use with non-main sexual partners (adjusted odds ratio = 2.3, 95% confidence interval = 1.3-4.0). There was no association between hopelessness and condom use with a main partner or sex with more than one partner in the past 3 months. These findings imply that hopelessness may encourage sexual risk-taking behavior in young males.

Mucins are gel-forming proteins that are responsible for the characteristic viscoelastic properties of mucus. Mucin overproduction is a hallmark of asthma, but the cellular requirements for airway mucin production are poorly understood. The endoplasmic reticulum (ER) protein anterior gradient homolog 2 (AGR2) is required for production of the intestinal mucin MUC2, but its role in the production of the airway mucins MUC5AC and MUC5B is not established. Microarray data were analyzed to examine the relationship between AGR2 and MUC5AC expression in asthma. Immunofluorescence was used to localize AGR2 in airway cells. Coimmunoprecipitation was used to identify AGR2-immature MUC5AC complexes. Agr2(-/-) mice were used to determine the role of AGR2 in allergic airway disease. AGR2 localized to the ER of MUC5AC- and MUC5B-producing airway cells and formed a complex with immature MUC5AC. AGR2 expression increased together with MUC5AC expression in airway epithelium from "Th2-high" asthmatics. Allergen-challenged Agr2(-/-) mice had greater than 50% reductions in MUC5AC and MUC5B proteins compared with allergen-challenged wild-type mice. Impaired mucin production in Agr2(-/-) mice was accompanied by an increase in the proportion of mucins contained within the ER and by evidence of ER stress in airway epithelium. This study shows that AGR2 increases with mucin overproduction in individuals with asthma and in mouse models of allergic airway disease. AGR2 interacts with immature mucin in the ER and loss of AGR2 impairs allergen-induced MUC5AC and MUC5B overproduction.