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1.  Inflammatory Dilated Cardiomyopathy in Abcg5 Deficient Mice 
Toxicologic pathology  2012;41(6):880-892.
Dilated cardiomyopathy (DCM) in A/J mice homozygous for the spontaneous thrombocytopenia and cardiomyopathy (trac) mutation results from a single base pair change in the Abcg5 gene. A similar mutation in humans causes sitosterolemia with high plant sterol levels, hypercholesterolemia, and early onset atherosclerosis. Analyses of CD3+ and Mac-3+ cells and trichrome stainable collagen in hearts showed inflammation and myocyte degeneration in A/J-trac/trac mice beginning post-weaning and progressed to marked dilative and fibrosing cardiomyopathy by 140 days. TEM demonstrated myocyte vacuoles consistent with swollen ER. Myocytes with abundant cytoplasmic glycogen and less dense actinomyosin filament bundles formed mature intercalated discs with adjacent normal myocytes suggesting myocyte repair. A/J-trac/trac mice fed life long phytosterol-free diets did not develop cardiomyopathy. BALB/cByJ- trac/trac mice had lesser inflammatory infiltrates and later onset DCM. BALB/cByJ- trac/trac mice changed from normal to phytosterol-free diets after initiation of cadiomyopathy had lesser T cell infiltrates but persistent monocyte infiltrates and equivalent fibrosis to mice on normal diets. B and T cell deficient BALB/cBy-Rag1null trac/trac mice fed normal diets did not develop inflammatory infiltrates or DCM. We conclude that DCM in the trac/trac mouse shares many features of inflammatory DCM and that the reversibility of myocardial T cell infiltration provides a novel model for investigating the progression of myocardial fibrosis.
PMCID: PMC3905339  PMID: 23129576
2.  Synergistic Up-Regulation of CXCL10 by Virus and IFN γ in Human Airway Epithelial Cells 
PLoS ONE  2014;9(7):e100978.
Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN γ and influenza virus. The synergism also occurred when the cells were treated with IFN γ and a viral replication mimicker (dsRNA) both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn’t affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFκB sites, western blot analysis indicated that the combined treatment of IFN γ and dsRNA significantly augmented NFκB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN γ and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFκB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level.
PMCID: PMC4102466  PMID: 25033426
3.  2,3,7,8-Tetrachlorodibenzo-p-dioxin–Induced MUC5AC Expression 
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxicant. Epidemiological studies have associated TCDD exposure with the development of chronic obstructive pulmonary disease, which is manifested by mucous/goblet cell hyperplasia. The purpose of this research was to elucidate the pathway/mechanisms that lead to TCDD-induced gene expression in both primary normal human bronchial epithelial cells and an immortalized cell line, HBE1, under air–liquid interface conditions. TCDD exposure induced a time-dependent elevation of MUC5AC mRNA and protein synthesis, and cytochrome p450 1A1 (CYP1A1) expression in these cells. Treatment with an aryl hydrocarbon receptor antagonist had no effect on TCDD-induced MUC5AC expression, but significantly suppressed CYP1A1 induction. However, treatments with inhibitors of signaling pathways and the expression of dominant negative mutants of epidermal growth factor receptor (EGFR), extracellular signal–regulated kinase (ERK) and p38, but not the inhibition of c-Jun N-terminal kinase pathway, abrogated MUC5AC induction, but not that of CYP1A1. These effects also occurred at the MUC5AC promoter–reporter level using the chimeric construct for a transient transfection study. Western blot analysis confirmed the phosphorylation of activated EGFR, ERK, and p38 signaling molecules, but not the c-Jun N-terminal kinase, in cells after TCDD exposure. Specificity protein 1 (Sp1) phosphorylation also occurred in cells after TCDD exposure. Both MUC5AC expression and the promoter activity were inhibited by mithramycin A, an inhibitor specific to Sp1-based transcription. These results lead to the conclusion that TCDD induced MUC5AC expression through a noncanonical aryl hydrocarbon receptor–independent, EGFR/ERK/p38–mediated signaling pathway–mediated/Sp1-based transcriptional mechanism.
PMCID: PMC3175556  PMID: 20971882
2,3,7,8-tetrachlorodibenzo-p-dioxin; aryl hydrocarbon receptor; airways; mucin; signaling
4.  Influenza-induced innate immunity: regulators of viral replication, respiratory tract pathology & adaptive immunity 
Future virology  2011;6(8):951-962.
Influenza virus infections usually cause mild to moderately severe respiratory disease, however some infections, like those involving the avian H5N1 virus, can cause massive viral pneumonia, systemic disease and death. The innate immune response of respiratory tract resident cells is the first line of defense and limits virus replication. Enhanced cytokine and chemokine production following infection, however, appears to underlie much of the pathology that develops after infection with highly pathogenic strains. A so-called `cytokine storm' can damage the lung tissue and cause systemic disease, despite the control of viral replication. By summarizing current knowledge of the innate responses mounted to influenza infection, this review highlights the importance of the respiratory tract epithelial cells as regulators of innate and adaptive immunity to influenza virus.
PMCID: PMC3168512  PMID: 21909336
antiviral immunity; cytokine; cytokine storm; influenza A; innate immunity; lung epithelium; respiratory tract; type I IFN; virulence
5.  Activation of Neurokinin-1 Receptors during Ozone Inhalation Contributes to Epithelial Injury and Repair 
We investigated the importance of neurokinin (NK)-1 receptors in epithelial injury and repair and neutrophil function. Conscious Wistar rats were exposed to 1 ppm ozone or filtered air for 8 hours, followed by an 8-hour postexposure period. Before exposure, we administered either the NK-1 receptor antagonist, SR140333, or saline as a control. Ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, whole mounts of airway dissected lung lobes were immunostained for 5-bromo-2′-deoxyuridine, a marker of epithelial proliferation. Both ethidium homodimer and 5-bromo-2′-deoxyuridine-positive epithelial cells were quantified in specific airway generations. Rats treated with the NK-1 receptor antagonist had significantly reduced epithelial injury and epithelial proliferation compared with control rats. Sections of terminal bronchioles showed no significant difference in the number of neutrophils in airways between groups. In addition, staining ozone-exposed lung sections for active caspase 3 showed no apoptotic cells, but ethidium-positive cells colocalized with the orphan nuclear receptor, Nur77, a marker of nonapoptotic, programmed cell death mediated by the NK-1 receptor. An immortalized human airway epithelial cell line, human bronchial epithelial-1, showed no significant difference in the number of oxidant stress–positive cells during exposure to hydrogen peroxide and a range of SR140333 doses, demonstrating no antioxidant effect of the receptor antagonist. We conclude that activation of the NK-1 receptor during acute ozone inhalation contributes to epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways.
PMCID: PMC2542446  PMID: 18390473
oxidant airway injury; neutrophil emigration; cell proliferation; neurokinin-1 receptor; nonapoptotic programmed cell death

Results 1-5 (5)