Ji-Hun Mo

Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells

The mechanisms by which commensal bacteria suppress inflammatory signalling in the gut are still unclear. Here, we present a cellular mechanism whereby the polarity of intestinal epithelial cells (IECs) has a major role in colonic homeostasis. TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-κB activation and cDNA microarray analysis. Whereas basolateral TLR9 signals IκBα degradation and activation of the NF-κB pathway, apical TLR9 stimulation invokes a unique response in which ubiquitinated IκB accumulates in the cytoplasm preventing NF-κB activation. Furthermore, apical TLR9 stimulation confers intracellular tolerance to subsequent TLR challenges. IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-κB activation threshold and these mice are highly susceptible to experimental colitis. Our data provide a case for organ-specific innate immunity in which TLR expression in polarized IECs has uniquely evolved to maintain colonic homeostasis and regulate tolerance and inflammation.

3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis

3-Hydroxyanthranilic acid (HAA), a compound generated during tryptophan metabolism initiated by indoleamine 2,3-dioxygenase, is known to induce T cell death, but its molecular target is not known. Here we report that HAA inhibits NF-κB activation upon T cell antigen receptor engagement by specifically targeting PDK1. Inhibition of NF-κB by HAA leads to dysfunction and cell death of activated Th2 cells, which in turn suppresses experimental asthma. Inhibition of NF-κB and induction of apoptosis is specific to CD4 T cells because HAA does not inhibit NF-κB activation or induce cell death upon Toll-like receptor 4 stimulation in dendritic cells. Thus, HAA is a natural inhibitor that restrains T cell expansion and activation.

Conventional dendritic cells regulate the outcome of colonic inflammation independently of T cells.

We explored the physiological role of conventional dendritic cells (cDCs) in acute colitis induced by a single cycle of dextran sodium sulfate administration. Depending on their mode of activation and independently of T cells, cDCs can enhance or attenuate the severity of dextran sodium sulfate-induced colitis. The latter beneficial effect was achieved, in part, by IFN-1 induced by Toll-like receptor 9-activated cDCs. IFN-1 inhibits colonic inflammation by regulating neutrophil and monocyte trafficking to the inflamed colon and restraining the inflammatory products of tissue macrophages. These data highlight a novel role of cDCs in the regulation of other innate immune cells and position them as major players in acute colonic inflammation.

Toll-like receptor signaling in intestinal epithelial cells contributes to colonic homoeostasis.

Purpose of review Since intestinal epithelium expresses Toll-like receptors, it was suggested that the intestinal epithelium is actively involved in the maintenance of colonic homeostasis. Here we describe our recent findings, which support an active contribution of colonic epithelium to intestinal homeostasis via a unique activation of epithelial TLR9. Recent findings Recent data indicate that stimulation of Toll-like receptors by intestinal microbiota supports colonic homeostasis. Several Toll-like receptors are expressed in intestinal epithelium. TLR9, an intracellular protein in immune cells, is expressed on the cell surfaces of intestinal epithelium, both on the apical and the basolateral membrane. TLR9 signaling varies in a domain-specific manner; whereas JNK is activated by TLR9 ligand both apically or basolaterally, NF-κB is activated only via basolateral stimulation. In apical TLR9 stimulation, IκB is phosphorylated and ubiquitinated but is not degraded, and NF-κB-dependent inflammatory signals are not transduced. Stimulation of apical TLR9 compromises the inflammatory cascade induced basolaterally by several other Toll-like receptor ligands, suggesting that apical exposure to luminal microbial DNA restrains intestinal inflammation. Summary These data indicate that certain luminal bacterial products support colonic homeostasis via activation of epithelial Toll-like receptors. The role of epithelial Toll-like receptor expression and activation in the pathogenesis of human inflammatory bowel disease is yet to be explored.

Determinants of treatment outcome after use of the mandibular advancement device in patients with obstructive sleep apnea.

OBJECTIVE To determine the predictors affecting treatment outcome after application of the mandibular advancement device (MAD). DESIGN Retrospective analysis. SETTING Tertiary care university hospital. PATIENTS A total of 76 patients (68 men and 8 women) who were treated with the MAD for obstructive sleep apnea (OSA) were included from September 2005 through August 2008. All the subjects underwent cephalometry, nocturnal polysomnography, and sleep videofluoroscopy (SVF) before and at least 3 months after receipt of a custom-made MAD. Sleep videofluoroscopy was performed before and after sleep induction and was analyzed during 3 states of awakeness, normoxygenation sleep, and desaturation sleep. Subjects were divided into success and nonsuccess groups depending on treatment outcome. MAIN OUTCOME MEASURES Multiple variables from cephalometry and SVF including the length of the soft palate, retropalatal space, retrolingual space, and mouth opening angle were evaluated during sleep events with or without the MAD between success and nonsuccess group. RESULTS The soft palate was significantly longer in the nonsuccess group than in the success group. The retropalatal and retrolingual airway spaces and mouth opening angle were not different between 2 groups. Application of the MAD increased the retrolingual space and decreased the length of the soft palate and the mouth opening angle significantly in both success and nonsuccess groups. However, retropalatal space was widened only in the success group, which showed that retropalatal space may be important in determining treatment response of the MAD. CONCLUSION The length of the soft palate showed a difference between success and nonsuccess groups, and widening of retropalatal space might be an important factor for successful outcome with MAD application.

An Investigation of Upper Airway Changes Associated With Mandibular Advancement Device Using Sleep Videofluoroscopy in Patients With Obstructive Sleep Apnea

OBJECTIVE To quantitatively evaluate the effects of the mandibular advancement device (MAD) on changes in the upper respiratory tract during sleep using sleep videofluoroscopy (SVF) in patients with obstructive sleep apnea (OSA). DESIGN Retrospective analysis. SETTING Academic tertiary referral center. PATIENTS Seventy-six patients (68 men and 8 women) who were treated with the MAD for OSA were included from September 1, 2005, through August 31, 2008. INTERVENTION All patients underwent nocturnal polysomnography and SVF before and at least 3 months after receipt of the custom-made MAD. Sleep videofluoroscopy was performed before and after sleep induction and was analyzed during 3 states of awakeness, normoxygenation sleep, and desaturation sleep. MAIN OUTCOME MEASURES Changes in the length of the soft palate, retropalatal space, retrolingual space, and angle of mouth opening were evaluated during sleep events with or without the MAD. RESULTS Without the MAD, the length of the soft palate and the angle of mouth opening increased during sleep events, especially in desaturation sleep, compared with the awake state. The retropalatal space and retrolingual space became much narrower during sleep compared with the awake state. The MAD had marked effects on the length of the soft palate, retropalatal space, retrolingual space, and angle of mouth opening. The retropalatal space and retrolingual space were widened, and the length of the soft palate was decreased. The MAD kept the mouth closed. CONCLUSIONS Sleep videofluoroscopy showed dynamic upper airway changes in patients with OSA, and the MAD exerted multiple effects on the size and configuration of the airway. Sleep videofluoroscopy demonstrated the mechanism of action of the MAD in patients with OSA. The MAD increased the retropalatal and retrolingual spaces and decreased the length of the soft palate and the angle of mouth opening, resulting in improvement of OSA.

Treatment of postviral olfactory loss with glucocorticoids, Ginkgo biloba, and mometasone nasal spray.

OBJECTIVE To analyze the efficacy of treating postviral olfactory loss with glucocorticoids, Ginkgo biloba, and mometasone furoate nasal spray. DESIGN Randomized trial. SETTING Academic research. PATIENTS Seventy-one patients who were diagnosed as having postviral olfactory loss. MAIN OUTCOME MEASURES All patients underwent olfactory function tests, including the butanol threshold test (BTT) and the cross-cultural smell identification test (CCSIT), and follow-up tests were performed 4 weeks later. In the interim, 28 patients were treated with prednisolone for 2 weeks (monotherapy), and the other 43 patients were treated with prednisolone for 2 weeks plus G biloba for 4 weeks (combination therapy). All patients used mometasone nasal spray twice daily for 4 weeks. RESULTS Scores on the BTT and CCSIT significantly increased after treatment in both groups (P < .001 for both). The mean (SD) BTT score changes were 1.4 (2.2) in the monotherapy group and 2.2 (2.9) in the combination therapy group (P = .22). The mean (SD) CCSIT score changes were 0.9 (1.7) in the monotherapy group and 1.9 (2.7) in the combination therapy group (P = .11). On the BTT, the treatment response (defined as a score increase of > or =3) rates were 32% (9 of 28) in the monotherapy group and 37% (16 of 43) in the combination therapy group (P = .66), and the odds ratio was 1.25 (95% confidence interval, 0.46-3.42). On the CCSIT, the treatment response rates were 14% (4 of 28) in the monotherapy group and 33% (14 of 43) in the combination therapy group (P = .08), and the odds ratio was 2.89 (95% confidence interval, 0.84-9.97). CONCLUSIONS Olfactory function in patients with postviral olfactory loss was significantly improved by both treatment modalities. Although the treatment response was not statistically different between the monotherapy group and the combination therapy group, the addition of G biloba showed a tendency of greater efficacy in the treatment of postviral olfactory loss.

Evaluation of Soft Palate Changes Using Sleep Videofluoroscopy in Patients With Obstructive Sleep Apnea

OBJECTIVE To quantitatively evaluate the changes in the soft palate (SP) by sleep videofluoroscopy (SVF). DESIGN Retrospective analysis. SETTING Academic tertiary referral center. PATIENTS A total of 63 consecutive patients with snoring or sleep apnea (53 with obstructive sleep apnea [OSA] and 10 simple snorers). INTERVENTIONS All the subjects underwent SVF and nocturnal polysomnography. Sleep videofluoroscopy was performed before and after sleep induction by intravenous injection of low-dose midazolam (2 mg per person) and was recorded during 3 kinds of events: awake, normoxygenation sleep, and desaturation sleep events. MAIN OUTCOME MEASURES Changes in SP length and the angle between inspiratory and expiratory efforts in each group were evaluated according to sleep events; changes in the SP was assessed according to obstruction sites and severity of OSA. RESULTS Desaturation sleep events were detected in all patients with OSA but not in simple snorers. In awake events, inspiratory efforts increased the length and angle of the SP in patients with OSA but not in simple snorers. Elongation and angulation were greatest during desaturation sleep events and least during awake events. In normoxygenation events, changes in the SP were significantly larger in patients with OSA than in simple snorers (P < .01 for SP length; P = .03 for SP angle). Elongation of the SP was the biggest in SP-type obstruction. CONCLUSIONS Sleep videofluoroscopy quantitatively showed that the SP was considerably elongated and angulated in patients with OSA even in an awake state. It is an easy way to measure the SP changes and may be a useful technique to differentiate OSA from simple snoring with short examination time.

Positional dependency in Asian patients with obstructive sleep apnea and its implication for hypertension.

OBJECTIVES To investigate the relationship of obstructive sleep apnea (OSA) with positional dependency and to identify its clinical implication in an Asian population. DESIGN Retrospective analysis. SETTING Academic tertiary referral center. PATIENTS A total of 1170 adults (1003 men and 167 women; mean [SD] age, 50.8 [12.9] years) with OSA were included from February 1, 2004, through October 31, 2008. INTERVENTION AND MAIN OUTCOME MEASURES All patients underwent full-night polysomnography. The anthropometric or polysomnographic variables between the patients with positional OSA (PPs) and those with nonpositional OSA (NPPs) were characterized, and multivariate analysis was performed to find the determining factors of positional dependency. The prevalence of hypertension was also investigated. RESULTS Nearly 75% of the patients (874 [74.7%]) had positional dependency. Positional dependency was present in 87.0% of the patients with mild OSA (apnea hypopnea index [AHI], ≥5 but <20), in 84.2% of those with moderate OSA (20 ≤ AHI < 40), and in 43.1% of those with severe OSA (AHI ≥ 40). The prevalence of PPs was 46.4% among severely obese patients (body mass index [BMI], ≥30, calculated as weight in kilograms divided by height in meters squared) and 82.7% among the nonobese patients (BMI < 25) and 74.6% among obese patients (25 ≤ BMI <30). Multivariate analysis showed that the AHI was the most dominant variable that determined positional dependency, followed by the BMI. In the PP group, the percentages of deep sleep and rapid eye movement sleep were significantly greater compared with those in the NPP group. The Epworth Sleepiness Scale score was lower in the PP group. The prevalence of hypertension was 34.4% and 49.7% in the PP and NPP groups, respectively. CONCLUSIONS This study demonstrates that the prevalence of PPs among Asians is almost three-fourths of the patients and that the AHI is the most dominant factor for determining positional dependency, followed by BMI. The PP group had lower BMI, a lower AHI, longer deep sleep, longer rapid eye movement sleep, and less daytime sleepiness than did the NPPs. The prevalence of hypertension was also affected by positional dependency.

The role of interleukin-33 in chronic rhinosinusitis.

Rationale Interleukin (IL)-33, a new member of the IL-1 family, is constitutively expressed in epithelial tissues and lymphoid organs and plays an important role in the pathogenesis of allergic disease. However, the role of IL-33 in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear. Objective To investigate the role of IL-33 in the pathophysiology of CRSwNP. Methods We investigated IL-33 expression and its cellular origins in the nasal polyps (NPs) of human subjects by immunohistochemistry (IHC), quantitative reverse transcription PCR (qRT-PCR), and multiplex cytokine assays. Correlations between IL-33 expression and other inflammatory markers were also explored. To investigate the role of IL-33 in CRSwNP, anti-IL-33 antibody was used in a murine model of CRS. Results Uncinate process tissues from control (19), CRSsNP (61), CRSwNP (69) and NP tissues (71) were used in this study. Increased expression of IL-33 mRNA and protein in patients with CRSwNP compared with controls was observed. The concentration of IL-33 protein in CRSwNP was positively correlated with the number of neutrophils and the expression of several Th1 and Th17 inflammatory markers, including interferon (IFN)-γ, IL-1β, tumour necrosis factor (TNF)-α, IL-17A, IL-22, and various markers for neutrophil recruitment. However, protein levels of IL-5 and quantity of eosinophils were inversely correlated with levels of IL-33. The expression of tissue inhibitor of metalloproteinase (TIMP)-1 was negatively correlated with IL-33 protein levels, while the expression of matrix metalloproteinase (MMP)-2 and MMP-9 was positively correlated with IL-33 protein levels. In animal studies, IL-33 expression was upregulated in the CRSwNP group compared with controls. Anti-IL-33 treatment reduced the thickness of oedematous mucosa, subepithelial collagen deposition, and infiltration of neutrophils, but infiltration of eosinophils was not reduced. This treatment also inhibited the expression of neutrophilic inflammatory cytokines, but not IL-4. In addition, the expression of intracellular adhesion molecule 1, vascular adhesion molecule 1 and CXCL-2 in the nasal mucosa was suppressed in mice treated with anti-IL-33 antibody. Conclusions Our data suggest a role for IL-33 in the pathogenesis of CRSwNP via neutrophil recruitment. Therefore, anti-IL-33 may provide a new treatment strategy to target infiltrating neutrophils in CRSwNP.