Bumseok Kim

Air Pollution Exposure and Cardiovascular Disease

Ambient air pollution (AAP) and particulate matters (PM) have been closely associated with adverse health effects such as respiratory disease and cardiovascular diseases. Previous studies have examined the adverse health effects associated with short- and long-term exposure to AAP and outdoor PM on respiratory disease. However, the effect of PM size (PM2.5 and PM10) on cardiovascular disease has not been well studied. Thus, it remains unclear how the size of the inhalable particles (coarse, fine, or ultrafine) affects mortality and morbidity. Airborne PM concentrations are commonly used for ambient air quality management worldwide, owing to the known effects on cardiorespiratory health. In this article, we assess the relationship between cardiovascular diseases and PM, with a particular focus on PM size. We discuss the association of PM2.5 and PM10, nitrogen dioxide (NO2), and elemental carbon with mortality and morbidity due to cardiovascular diseases, stroke, and altered blood pressure, based on epidemiological studies. In addition, we provide evidence that the adverse health effects of AAP and PM are more pronounced among the elderly, children, and people with preexisting cardiovascular and respiratory conditions. Finally, we critically summarize the literature pertaining to cardiovascular diseases, including atherosclerosis and stroke, and introduce potential studies to better understand the health significance of AAP and PM on cardiovascular disease.

Role of Interferon in Homologous and Heterologous Rotavirus Infection in the Intestines and Extraintestinal Organs of Suckling Mice

ABSTRACT Recent studies demonstrated that viremia and extraintestinal rotavirus infection are common in acutely infected humans and animals, while systemic diseases appear to be rare. Intraperitoneal infection of newborn mice with rhesus rotavirus (RRV) results in biliary atresia (BA), and this condition is influenced by the host interferon response. We studied orally inoculated 5-day-old suckling mice that were deficient in interferon (IFN) signaling to evaluate the role of interferon on the outcome of local and systemic infection after enteric inoculation. We found that systemic replication of RRV, but not murine rotavirus strain EC, was greatly enhanced in IFN-α/β and IFN-γ receptor double-knockout (KO) or STAT1 KO mice but not in mice deficient in B- or T-cell immunity. The enhanced replication of RRV was associated with a lethal hepatitis, pancreatitis, and BA, while no systemic disease was observed in strain EC-infected interferon-deficient mice. In IFN-α/β receptor KO mice the extraintestinal infection and systemic disease were only moderately increased, while RRV infection was not augmented and systemic disease was not present in IFN-γ receptor KO mice. The increase of systemic infection in IFN-deficient mice was also observed during simian strain SA11 infection but not following bovine NCDV, porcine OSU, or murine strain EW infection. Our data indicate that the requirements for the interferon system to inhibit intestinal and extraintestinal viral replication in suckling mice vary among different heterologous and homologous rotavirus strains, and this variation is associated with lethal systemic disease.

Enteric Viruses Ameliorate Gut Inflammation via Toll-like Receptor 3 and Toll-like Receptor 7-Mediated Interferon-β Production

Metagenomic studies show that diverse resident viruses inhabit the healthy gut; however, little is known about the role of these viruses in the maintenance of gut homeostasis. We found that mice treated with antiviral cocktail displayed more severe dextran sulfate sodium (DSS)-induced colitis compared with untreated mice. DSS-induced colitis was associated with altered enteric viral abundance and composition. When wild-type mice were reconstituted with Toll-like receptor 3 (TLR3) or TLR7 agonists or inactivated rotavirus, colitis symptoms were significantly ameliorated. Mice deficient in both TLR3 and TLR7 were more susceptible to DSS-induced experimental colitis. In humans, combined TLR3 and TLR7 genetic variations significantly influenced the severity of ulcerative colitis. Plasmacytoid dendritic cells isolated from inflamed mouse colon produced interferon-β in a TLR3 and TLR7-dependent manner. These results imply that recognition of resident viruses by TLR3 and TLR7 is required for protective immunity during gut inflammation.

A genetically engineered derivative of Salmonella Enteritidis as a novel live vaccine candidate for salmonellosis in chickens

To construct a novel live Salmonella Enteritidis (SE) vaccine candidate, SE was genetically engineered using the allelic exchange method to delete two virulence genes, lon and cpxR. The lon gene deletion is essential to impair Salmonella replication and avoid overwhelming systemic disease in the host. The cpxR gene deletion is needed to enhance the ability of bacteria to adhere and invade the host cell. Scanning electron microscopy revealed that the derivatives JOL917 (Δlon), JOL918 (ΔcpxR), and JOL919 (Δlon/ΔcpxR) had increased surface fimbrial filamentous structures. Significant elevations of extracellular polysaccharide and FimA expression were observed for the derivatives compared to the parental wild type JOL860, while biochemical properties of the derivatives were not altered. In the safety examination by inoculation of the derivatives in chickens, gross lesion scores of the liver, spleen, kidney, small intestine and caecal tonsils were moderate in the JOL917 and JOL918 groups, and significantly lower in the JOL919 group than those of the JOL860. Bacterial counts from the spleen and caeca of the JOL917 and JOL918 groups were moderate, and significantly reduced in the JOL919 group compared to the JOL860 group. In addition, only the JOL919 group showed significantly lower bacterial counts in the faecal samples than those of the JOL860 group. Significant elevations of IgG and secretory IgA levels observed in the derivative groups, while the JOL919 and JOL860 groups showed a potent lymphocyte proliferation response as compared to those of the control group. In the protection efficacy examination, JOL919 immunized group showed significantly lower depression, lower gross lesion in the liver and spleen, and lower number of the SE positive internal organs than those of the control group against a virulent wild type SE challenge.

Fabrication of borassus fruit lignocellulose fiber/PP composites and comparison with jute, sisal and coir fibers.

Novel composites based on borassus fruit fine fiber (BFF) and polypropylene (PP) were fabricated with variable fiber composition (5, 10, 15 and 20 wt%) by injection molding. Maleated PP (MAPP) was also used as compatibilizer at 5 wt% for effective fiber-matrix adhesion. FTIR analysis confirms the evidence of a chemical bonding between the fiber and polymeric matrix through esterification in presence of MAPP. The tensile and flexural properties were found to increase with 15 and 10 wt% fiber loadings respectively, and decreased thereafter. Coir, jute and sisal fiber composites were also fabricated with 15 wt% fiber loading under the same conditions as used for BFF/PP composites. It was found that the mechanical properties of BFF (15 wt%)/PP composites were equivalent to jute/PP, sisal/PP and superior to coir/PP composites. Jute/PP and sisal/PP composites showed higher water absorption than BFF/PP and coir/PP composites. These results have demonstrated that the BFF/PP composites can also be an alternative material for composites applications.

Multifront assault on antigen presentation by Japanese encephalitis virus subverts CD8+ T cell responses.

Japanese encephalitis virus (JEV) is a frequent cause of acute and epidemic viral encephalitis. However, there is little information describing the mechanisms by which JEV subverts immune responses that may predispose the host to secondary infections. In this study, we found that JEV induced the subversion of CD8+ T cell responses in a transient manner that was closely correlated with viral multiplication. Subsequently, analysis using a TCR-transgenic system revealed that CD8+ T cells purified from JEV-infected mice showed impaired responses, and that naive CD8+ T cells adoptively transferred into JEV-infected recipients showed less expanded responses. Furthermore, JEV altered the splenic dendritic cell (DC) subpopulation via preferential depletion of CD8α+CD11c+ DCs without changing the plasmacytoid DCs and induced a significant reduction in the surface expression of MHC class II and CD40, but not MHC class I, CD80, and CD86 molecules. Finally, JEV was shown to inhibit the presentation of MHC class I-restricted Ag in DCs, and this immune suppression was ameliorated via the activation of DCs by TLR agonists. Collectively, our data indicate that JEV precludes the functions of Ag-presenting machinery, such as depletion of CD8α+CD11c+ DCs and downregulation of MHC class I-restricted Ag presentation, thereby leading to immune subversion of CD8+ T cells.

Toll-like receptor 7-mediated Type I Interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis

Toll‐like receptor 7 (TLR7) signaling predominantly regulates production of type I interferons (IFNs), which has been suggested in clinical studies to be antifibrotic. However, the mechanistic role of the TLR7‐type I IFN axis in liver fibrosis has not been elucidated. In the present study, liver fibrosis was induced in wild‐type (WT), TLR7‐deficient, and IFN‐α/β receptor‐1 (IFNAR1)‐deficient mice and TLR7‐mediated signaling was assessed in liver cells isolated from these mice. TLR7‐deficient and IFNAR1‐deficient mice were more susceptible to liver fibrosis than WT mice, indicating that TLR7‐type I IFN signaling exerts a protective effect against liver fibrosis. Notably, the hepatic expression of interleukin‐1 receptor antagonist (IL‐1ra) was suppressed in TLR7‐ or IFNAR1‐deficient mice compared with respective WT mice, and treatment with recombinant IL‐1ra reduced liver fibrosis. In vivo activation of TLR7 significantly increased IFNa4 and IL‐1ra expression in the liver. Interestingly, each cytokine had a different cellular source, showing that dendritic cells (DCs) are the responsible cell type for production of type I IFN, while Kupffer cells (KCs) mainly produce IL‐1ra in response to type I IFN. Furthermore, TLR7 activation by R848 injection suppressed liver fibrosis and production of proinflammatory cytokines, and these effects were dependent on type I IFN signaling. Consistent with in vivo data, IFN‐α significantly induced IL‐1ra production in primary KCs. Conclusion: TLR7 signaling activates DCs to produce type I IFN, which in turn induces antifibrogenic IL‐1ra production in KCs. Thus, manipulation of the TLR7‐type I IFN‐IL‐1ra axis may be a new therapeutic strategy for the treatment of liver fibrosis. (Hepatology 2014;60:237–249)

Upregulation of heme oxygenase-1 by ginsenoside Ro attenuates lipopolysaccharide-induced inflammation in macrophage cells.

Background The beneficial effects of ginsenoside species have been well demonstrated in a number of studies. However, the function of ginsenoside Ro (GRo), an oleanane-type saponin, has not been sufficiently investigated. Thus, the aim of the present study was to investigate the anti-inflammatory effects of GRo in vitro using the Raw 264.7 mouse macrophage cell line treated with lipopolysaccharide (LPS), and to clarify the possible mechanism of GRo involving heme oxygenase-1 (HO-1), which itself plays a critical role in self-defense in the presence of inflammatory stress. Methods Raw 264.7 cells were pretreated with GRo (up to 200μM) for 1 h before treatment with 1 μg/mL LPS, and both cell viability and inflammatory markers involving HO-1 were evaluated. Results GRo significantly increased cell viability in a dose dependent manner following treatment with LPS, and decreased levels of reactive oxygen species and nitric oxide. GRo decreased inflammatory cytokines such as nitric oxide synthase and cyclooxygenase-2 induced by LPS. Moreover, GRo increased the expression of HO-1 in a dose dependent manner. Cotreatment of GRo with tin protoporphyrin IX, a selective inhibitor of HO-1, not only inhibited upregulation of HO-1 induced by GRo, but also reversed the anti-inflammatory effect of GRo in LPS treated Raw 264.7 cells. Conclusion GRo induces anti-inflammatory effects following treatment with LPS via upregulation of HO-1.

The Role of Air Pollutants in Initiating Liver Disease

Recent episodes of severe air pollution in eastern Asia have been reported in the scientific literature and news media. Therefore, there is growing concern about the systemic effects of air pollution on human health. Along with the other well-known harmful effects of air pollution, recently, several animal models have provided strong evidence that air pollutants can induce liver toxicity and act to accelerate liver inflammation and steatosis. This review briefly describes examples where exposure to air pollutants was involved in liver toxicity, focusing on how particulate matter (PM) or carbon black (CB) may be translocated from lung to liver and what liver diseases are closely associated with these air pollutants.

Differential immune modulation by deoxynivalenol (vomitoxin) in mice.

Mycotoxin deoxynivalenol (DON), a secondary metabolite produced by Fusarium fungi, is a contaminant in wheat, barley, and corn worldwide. It has been suggested that DON exhibits toxicity in various organs. Due to the lack of immunotoxicity data for DON, we investigated the differential immunomodulatory effects of DON in mice. DON was orally administered to female BALB/c mice at a dose of 0, 0.5, or 2mg/kg body weight for 14 days and various immunotoxicity tests were performed with standard protocols. The population of CD19(+) and CD11c(+) cells in the spleen and mesenteric lymph node (MLN) and of F4/80(+) cells in the spleen was significantly decreased in DON-treated mice, whereas the level of CD8(+) and CD4(+)CD25(+)Foxp3(+) cells in the spleen and CD4(+) T cells in MLN was significantly increased. In intra-epithelial lymphocytes (IELs) of the small intestine, the population of CD4 (+) and CD19(+) cells was increased but that of CD8(+) cells was decreased. Levels of CD4 (+) and CD8(+) cells were decreased in lamina propria lymphocytes (LPLs) of small intestine; however, the level of CD4(+) and CD8(+) lymphocytes was increased but that of CD19(+) cells was decreased in Peyers patches lymphocytes (PPLs). Normalized expression of TLR4 in spleen, TLR9 in PPs, and TLR2, TLR3 and TLR4 in MLNs was significantly decreased, whereas expression of TLR5 and TLR9 was increased in spleen. The concentration of IgA and IgE was decreased and increased, respectively, in serum; however, the mucosal IgA level was significantly increased in the duodenum. Levels of IFN-γ, IL-2, IL-4, and IL-6 were significantly increased in serum. Furthermore, DON induced apoptosis in spleen, MLNs, and PPs, and DON-induced apoptosis was promoted by increased expression of Bax and decreased expression of Bcl-2. The autophagy genes Atg5 and Beclin-1 were up-regulated in spleen but down-regulated in MLN. After priming of the RAW 264.7 macrophage cell line with different TLR ligands, DON exposure differentially modulated IL-1β, IL-10, and TNF-α production. These results indicate that DON can cause various immunomodulatory effects in mice, creating a milieu that might allow invasion by other microorganisms.