Chang-Hung Kuo

Early life exposure to antibiotics and the risk of childhood allergic diseases: an update from the perspective of the hygiene hypothesis.

The prevalence of allergic diseases has been growing rapidly in industrial countries during recent decades. It is postulated that growing up with less microbial exposure may render the immune system susceptible to a T helper type 2 (Th2)-predominant allergic response-also known as the hygiene hypothesis. This review delineates recent epidemiological and experimental evidence for the hygiene hypothesis, and integrates this hypothesis into the association between early life exposure to antibiotics and the development of allergic diseases and asthma. Several retrospective or prospective epidemiological studies reveal that early exposure to antibiotics may be positively associated with the development of allergic diseases and asthma. However, the conclusion is inconsistent. Experimental studies show that antibiotics may induce the Th2-skewed response by suppressing the T helper type 1 (Th1) response through inhibition of Th1 cytokines and disruption of the natural course of infection, or by disturbing the microflora of the gastrointestinal (GI) tract and therefore jeopardizing the establishment of oral tolerance and regulatory T cell immune responses. The hygiene hypothesis may not be the only explanation for the rapid increase in the prevalence of allergic diseases and asthma. Further epidemiological and experimental studies addressing the issue of the impact of environmental factors on the development of allergic diseases and the underlying mechanisms may unveil novel strategies for the prevention and treatment of allergic diseases in the future.

Immunomodulatory effects of environmental endocrine disrupting chemicals

During recent decades more than 100,000 new chemicals have been introduced as common consumer products into our environment. Among these chemicals, endocrine‐disrupting chemicals (EDCs) are of particular concern owing to their toxicity in animal studies and their impacts on human health. EDCs are ubiquitous in the environment, including the air, water, and soil. The endocrine‐disrupting effect of EDCs has been found to imitate the action of steroid hormones and promote several endocrine and reproductive disorders in both animal and human studies. In the present review, we focus on the effects of EDCs on the immune system. EDCs interfere with the synthesis of cytokines, immunoglobulins, and inflammatory mediators, and they also affect the activation and survival of immune cells. The dysfunction of the immune system caused by EDCs may lead to the attenuation of immunity (immunodeficiency) against infection or hyperreactivity of immune responses (allergy and autoimmune disease). In this review, we summarize epidemiologic, animal, and cell studies to demonstrate the potential effects of EDCs on immunity, allergy, and autoimmune diseases. We also address the impact of EDCs on epigenetic regulation.

The effects of environmental toxins on allergic inflammation.

The prevalence of asthma and allergic disease has increased worldwide over the last few decades. Many common environmental factors are associated with this increase. Several theories have been proposed to account for this trend, especially those concerning the impact of environmental toxicants. The development of the immune system, particularly in the prenatal period, has far-reaching consequences for health during early childhood, and throughout adult life. One underlying mechanism for the increased levels of allergic responses, secondary to exposure, appears to be an imbalance in the T-helper function caused by exposure to the toxicants. Exposure to environmental endocrine-disrupting chemicals can result in dramatic changes in cytokine production, the activity of the immune system, the overall Th1 and Th2 balance, and in mediators of type 1 hypersensitivity mediators, such as IgE. Passive exposure to tobacco smoke is a common risk factor for wheezing and asthma in children. People living in urban areas and close to roads with a high volume of traffic, and high levels of diesel exhaust fumes, have the highest exposure to environmental compounds, and these people are strongly linked with type 1 hypersensitivity disorders and enhanced Th2 responses. These data are consistent with epidemiological research that has consistently detected increased incidences of allergies and asthma in people living in these locations. During recent decades more than 100,000 new chemicals have been used in common consumer products and are released into the everyday environment. Therefore, in this review, we discuss the environmental effects on allergies of indoor and outside exposure.

Epigenetic regulation in allergic diseases and related studies

Asthma, a chronic inflammatory disorder of the airway, has features of both heritability as well as environmental influences which can be introduced in utero exposures and modified through aging, and the features may attribute to epigenetic regulation. Epigenetic regulation explains the association between early prenatal maternal smoking and later asthma-related outcomes. Epigenetic marks (DNA methylation, modifications of histone tails or noncoding RNAs) work with other components of the cellular regulatory machinery to control the levels of expressed genes, and several allergy- and asthma-related genes have been found to be susceptible to epigenetic regulation, including genes important to T-effector pathways (IFN-γ, interleukin [IL] 4, IL-13, IL-17) and T-regulatory pathways (FoxP3). Therefore, the mechanism by which epigenetic regulation contributes to allergic diseases is a critical issue. In the past most published experimental work, with few exceptions, has only comprised small observational studies and models in cell systems and animals. However, very recently exciting and elegant experimental studies and novel translational research works were published with new and advanced technologies investigating epigenetic mark on a genomic scale and comprehensive approaches to data analysis. Interestingly, a potential link between exposure to environmental pollutants and the occurrence of allergic diseases is revealed recently, particular in developed and industrialized countries, and endocrine disrupting chemicals (EDCs) as environmental hormone may play a key role. This review addresses the important question of how EDCs (nonylphenol, 4 octylphenol, and phthalates) influences on asthma-related gene expression via epigenetic regulation in immune cells, and how anti-asthmatic agents prohibit expression of inflammatory genes via epigenetic modification. The discovery and validation of epigenetic biomarkers linking exposure to allergic diseases might lead to better epigenotyping of risk, prognosis, treatment prediction, and development of novel therapies.

Tacrolimus suppresses atopic dermatitis-associated cytokines and chemokines in monocytes

BACKGROUND Calcineurin inhibitors (CNIs) exhibit remarkable efficacy in atopic dermatitis (AD). Tacrolimus, one type of CNI, is prevalently used to treat AD. AD is a chronic inflammatory disease that exhibits predominant infiltration of T-helper type 2 (Th2) cell in the acute phase and a mixed Th1 and Th0 cell pattern in chronic lesions. Cytokines such as tumor necrosis factor-α (TNF-α), Th2-related chemokines [e.g., macrophage-derived chemokine (MDC)/CCL22 and I-309/CCL1], Th1-related chemokines [e.g., interferon γ-induced protein 10 (IP-10)/CXCL10], and neutrophil chemoattractant growth-related oncogene-α (GRO-α)/CXCL1 are involved in the pathogenesis of AD. However, whether tacrolimus modulates the expression of AD-associated cytokines and chemokines remains unknown. The intracellular mechanisms of tacrolimus are also unclear. METHODS Human monocytic cell line THP-1 cells were pretreated with tacrolimus and stimulated with lipopolysaccharide (LPS). The MDC, I-309, IP-10, GRO-α, and TNF-α concentrations of the cell supernatants were measured using enzyme-linked immunosorbent assay. Intracellular signaling was investigated using the Western blot analysis. RESULTS Tacrolimus suppressed the expression of MDC, IP-10, I-309, GRO-α, and TNF-α in LPS-stimulated THP-1 cells in a dose- and time-dependent manner. All three mitogen-activated protein kinase (MAPK) inhibitors and the nuclear factor-κB inhibitor suppressed LPS-induced MDC, I-309, and TNF-α expressions in THP-1 cells. Only MAPK inhibitors suppressed LPS-induced expression of IP-10 and GRO-α. Tacrolimus suppressed the LPS-induced phosphorylation of MAPK-extracellular signal-related kinase (ERK). CONCLUSION Tacrolimus suppressed LPS-induced MDC, I-309, IP-10, GRO-α, and TNF-α expressions in monocytes through the MAPK-ERK pathway; thus, tacrolimus may yield therapeutic efficacy by modulating AD-associated cytokines and chemokines.

Tumor necrosis factor-alpha inhibitors suppress CCL2 chemokine in monocytes via epigenetic modification

&NA; The treatment of rheumatoid arthritis (RA) with tumor necrosis factor‐alpha (TNF‐&agr;) inhibitors could lead to adverse effects. Therefore, the identification of downstream therapeutic targets is important. Monocyte chemoattractant protein‐1 (MCP‐1, also called CCL2) is related to RA disease activity, and epigenetic modifications are hypothesized to regulate gene expression in RA pathogenesis. We studied the effects of two TNF‐&agr; inhibitors, etanercept and adalimumab, on CCL2 expression and the potentially associated intracellular mechanisms, including epigenetic regulation. Etanercept and adalimumab decreased CCL2 production in THP‐1 cells and human primary monocytes, as detected using enzyme‐linked immunosorbent assays, and these changes in the CCL2 levels were independent of the TNF‐&agr; levels. Etanercept and adalimumab suppressed mitogen‐activated protein kinase (MAPK) phospho‐p38, phospho‐JNK, phospho‐ERK and nuclear factor‐&kgr;B (NF‐&kgr;B) phospho‐p65, as demonstrated using western blot analyses. The investigation of epigenetic modifications using chromatin immunoprecipitation revealed that etanercept and adalimumab down‐regulated acetylation of histone (H)3 and H4 in the CCL2 promoter region by decreasing the recruitment of the NF‐&kgr;B associated acetyltransferases p300, CBP and PCAF. Etanercept and adalimumab also down‐regulated trimethylation of H3K4, H3K27, H3K36 and H3K79 in the CCL2 promoter region by decreasing the expression of the related methyltransferases WDR5 and Smyd2. We demonstrated that TNF‐&agr; inhibitors exert immunomodulatory effects on CCL2 expression in human monocytes via MAPKs, NF‐&kgr;B and epigenetic modifications. These findings broaden the mechanistic knowledge related to TNF‐&agr; inhibitors and provide novel therapeutic targets for RA. Graphical abstract Figure. No caption available. HighlightsTNF‐&agr; inhibitors suppress CCL2 production in human monocytes.TNF‐&agr; inhibitors suppress CCL2 through MAPK and p65‐NF&kgr;B pathways.TNF‐&agr; inhibitors downregulate the histone acetylation in the CCL2 promoter.TNF‐&agr; inhibitors downregulate the histone trimethylation in the CCL2 promoter.

Effect of prostaglandin I2 analogs on monocyte chemoattractant protein-1 in human monocyte and macrophage.

Abstract Chemokines play essential roles during inflammatory responses and in pathogenesis of inflammatory diseases. Monocyte chemotactic protein-1 (MCP-1) is a critical chemokine in the development of atherosclerosis and acute cardiovascular syndromes. MCP-1, by its chemotactic activity, causes diapedesis of monocytes from the lumen to the subendothelial space that leads to atherosclerotic plaque formation. Prostaglandin I2 (PGI2) analogs are used clinically for patients with pulmonary hypertension and have anti-inflammatory effects. However, little is known about the effect of PGI2 analogs on the MCP-1 production in human monocytes and macrophages. We investigated the effects of three conventional (iloprost, beraprost and treprostinil) and one new (ONO-1301) PGI2 analogs, on the expression of MCP-1 expression in human monocytes and macrophages. Human monocyte cell line, THP-1 cell, was treated with PGI2 analogs after LPS stimulation. Supernatants were harvested to measure MCP-1 levels and measured by ELISA. To explore which receptors involved the effects of PGI2 analogs on the expression of MCP-1 expression, IP and EP, PPAR-α and PPAR-γ receptor antagonists were used. Forskolin, a cAMP activator, was used to further confirm the involvement of cAMP on MCP-1 production in human monocytes. Three PGI2 analogs suppressed LPS-induced MCP-1 production in THP-1 cells and THP-1-induced macrophages. Higher concentrations of ONO-1301 also had the suppressive effect. CAY 10449, an IP receptor antagonist, could reverse the effects on MCP-1 production of iloprost on THP-1 cells. Other reported PGI2 receptor antagonists including EP1, EP2, EP4, PPAR-α and PPAR-γ antagonists could not reverse the effect. Forskolin, a cAMP activator, also suppressed MCP-1 production in THP-1 cells. PGI2 analogs suppressed LPS-induced MCP-1 production in human monocytes and macrophages via the IP receptor and cAMP pathway. The new PGI2 analog (ONO-1301) was not better than conventional PGI2 analog in the suppression of MCP-1 production in human monocytes.

Septic arthritis as the initial manifestation of fatal Vibrio vulnificus septicemia in a patient with thalassemia and iron overload.

Vibrio vulnificus infection is an uncommon but potentially fatal disease in children such that prompt recognition has prognostic implications. We describe here the case of a 9‐year‐old female with thalassemia and iron overload who presented with septic arthritis as an atypical initial manifestation of fatal V. vulnificus septicemia. This report underscores the possibility of septic arthritis as an early manifestation of V. vulnificus septicemia. Pediatricians should be alert to this extremely invasive disease, especially in children with iron overload. Pediatr Blood Cancer 2009;53:1156–1158.

The Effects of Asthma Medications on Reactive Oxygen Species Production in Human Monocytes

ABSTRACT Objective: Asthma is a chronic inflammatory airway disease induced by many environmental factors. The inhalation of allergens and pollutants promotes the production of reactive oxygen species (ROS) leading to airway inflammation, hyper-responsiveness, and remodeling in allergic asthma. The effects of asthma medications on ROS production are unclear. The present study investigated the anti-ROS effects of current asthma medications including inhaled corticosteroid (ICS; budesonide and fluticasone), leukotriene receptor antagonist (LTRA; montelukast), long-acting β2 agonists (LABAs; salmeterol and formoterol), and a new extra-LABA (indacaterol). Methods: The human monocyte cell line THP-1 cells were pre-treated with different concentrations of the asthma medications at different time points after hydrogen peroxide (H2O2) stimulation. H2O2 production was measured with DCFH-DA by flow cytometry. Results: Montelukast, fluticasone, and salmeterol suppressed H2O2-induced ROS production. Indacaterol enhanced H2O2-induced ROS production. Budesonide and formoterol alone had no anti-ROS effects, but the combination of these two drugs significantly suppressed H2O2-induced ROS production. Conclusions: Different asthma medications have different anti-ROS effects on monocytes. The combination therapy with LABA and ICS seemed not to be the only choice for asthma control. Montelukast may also be a good supplemental treatment for the poorly controlled asthma because of its powerful anti-ROS effects. Our findings provide a novel therapeutic view in asthma.

Co-existence of Posttraumatic Empyema Thoracis and Lung Abscess in a Child After Blunt Chest Trauma: A Case Report

Posttraumatic empyema is a rare complication of trauma with an incidence of 1.6–2.4% in trauma patients. However, it is rarely reported in children. We report the case of a 15‐year‐old boy who was involved in a traffic accident and diagnosed with a pulmonary contusion at a local hospital. Fourteen days after the accident, posttraumatic empyema thoracis and lung abscess developed with clinical presentations of fever, productive cough and right chest pain. He was successfully treated with computed tomography‐guided catheter drainage and intravenous cefotaxime. We emphasize that posttraumatic empyema thoracis and lung abscess are very rare in children, and careful follow‐up for posttraumatic lung contusion is essential. Image‐guided catheter drainage can be an adjunctive tool for treating selected patients, although most complicated cases of post‐traumatic empyema thoracis require decortication therapy.