Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner. Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E 4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design. Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a .18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E 4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge. Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E 4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P , 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P , 0.001). Conclusions: Omalizumab treatment inhibited urinary leukotriene E 4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.
Ovarian cancer G protein-coupled receptor 1 (OGR1) stimulation by extracellular protons causes the activation of G proteins and subsequent cellular functions. However, the physiological and pathophysiological roles of OGR1 in airway responses remain largely unknown. In the present study, we show that OGR1-deficient mice are resistant to the cardinal features of asthma, including airway eosinophilia, airway hyperresponsiveness (AHR), and goblet cell metaplasia, in association with a remarkable inhibition of Th2 cytokine and IgE production, in an ovalbumin (OVA)-induced asthma model. Intratracheal transfer to wild-type mice of OVA-primed bone marrow-derived dendritic cells (DCs) from OGR1-deficient mice developed lower AHR and eosinophilia after OVA inhalation compared with the transfer of those from wild-type mice. Migration of OVA-pulsed DCs to peribronchial lymph nodes was also inhibited by OGR1 deficiency in the adoption experiments. The presence of functional OGR1 in DCs was confirmed by the expression of OGR1 mRNA and the OGR1-sensitive Ca2+ response. OVA-induced expression of CCR7, a mature DC chemokine receptor, and migration response to CCR7 ligands in an in vitro Transwell assay were attenuated by OGR1 deficiency. We conclude that OGR1 on DCs is critical for migration to draining lymph nodes, which, in turn, stimulates Th2 phenotype change and subsequent induction of airway inflammation and AHR.
Proliferation in cholesteatoma epidermal cells is not uncontrolled, as it is in malignant tumors. Our results demonstrate an increase in the rate of proliferation and apoptotic cell death in cholesteatoma epidermis.
The PI3K family is thought to participate in TLR signaling, and it has been reported to be a negative regulator of TLR-mediated production of IL-12, a key inducer of Th1 responses. However, the role of individual PI3K subtypes in IL-12 production remains obscure. We defined the distinct regulation of LPS-mediated IL-12 production by p110α and p110β catalytic subunits of PI3K in human APCs. We observed that knockdown of PI3K p110β by small interfering RNA (siRNA) suppressed both LPS-induced IL-12 protein production and mRNA expression in monocyte-derived macrophages and dendritic cells (DCs). Knockdown of PI3K p110α by siRNA reduced LPS-induced IL-12 protein production in both cell types. Conversely, knockdown of PI3K p110α suppressed LPS-induced IL-12 mRNA expression in monocyte-derived macrophages but minimally affected monocyte-derived DCs. PI3K p110β siRNA inhibited JNK activation, but not p38 MAPK or ERK activation, stimulated by LPS, while PI3K p110α siRNA did not affect LPS-induced JNK, p38 MAPK, or ERK activation in both cell types. Transfection of siRNA against JNK1, JNK2, and both decreased LPS-induced IL-12 production. Furthermore, PI3K p110β siRNA attenuated LPS-induced JNK1 phosphorylation, while not affecting JNK2 phosphorylation. Our findings indicate that PI3K p110β positively controls LPS-induced IL-12 production through the JNK1-dependent pathway in human macrophages and DCs.
With the objective of estimating proliferation ability of epidermis of middle ear cholesteatoma, the difference in proliferating cell nuclear antigen (PCNA) staining between the skin of the bone region of the external ear canal (control skin) and cholesteatoma epidermis and the effects on PCNA staining of subepidermal inflammatory cell infiltration of cholesteatoma were immunohistochemically studied using an antibody against PCNA. Transforming growth factor-alpha (TGF-alpha) is known to promote epidermal proliferation based on autocrine mechanism. But it is not clear that cholesteatoma epidermis is actually in the state of hyperproliferation under the effect of this growth factor. To estimate the effect of TGF-alpha on epidermal proliferation ability, the authors compared the location of PCNA and TGF-alpha in the same specimen. Unlike the control skin, not only epidermal basal cell layer and suprabasal cell layer, but also more superior layers were found to have high levels of PCNA staining in the epidermis of cholesteatoma. However, in the same cholesteatoma epidermal tissue, the PCNA staining was varied and the difference was ascribable to subepidermal cell inflammation. It appeared that the proliferation ability was high in regions where subepidermal inflammatory cell infiltration was severe. These differences in microenvironment are inferred to greatly affect proliferation ability of cholesteatoma epidermis.
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