Background: Chemotactic cytokines, referred to as chemokines, play an important role in leukocyte trafficking. The circulating levels of chemokines have been shown to increase in inflammatory processes including obesity-related pathologies (e.g. atherosclerosis and diabetes). However, little is currently known about the relationship between chemokines and human obesity. In the present study, we investigated the circulating levels of selected chemokines (monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1a (MIP-1a), leukotactin-1, interleukin-8 (IL-8)) and the association between the chemokine levels and obesity-related parameters: body mass index (BMI), waist circumference, fasting glucose and insulin levels, lipids profile, and the level of C-reactive protein (CRP). Methods: A total of 100 subjects, 50 obese (BMIX25 kg/m 2 ) and 50 who were not obese (BMIo25 kg/m 2 ) participated in the present study. The levels of chemokines and CRP were measured in a fasting state serum by sandwich enzyme-linked immunosorbent assay. Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, glucose, and insulin levels were measured by enzymatic analysis and immunoassay. Results: The circulating levels of MCP-1 and IL-8 in the serum were significantly (Po0.05) higher in obese subjects (BMI430 kg/ m 2 ) compared with those of nonobese controls (BMIo25 kg/m 2 ). The levels of CRP were positively correlated with BMI (Po0.001) or waist circumference (Po0.0001). The levels of MCP-1 and IL-8 were positively related to BMI (MCP-1, Po0.02; IL-8, Po0.01) and/or waist circumference (MCP-1, Po0.009; IL-8, Po0.03). The levels of MCP-1 were positively related to the levels of CRP (Po0.007) or interleukin-6 (IL-6) (Po0.0001), and negatively related to the levels of HDL-cholesterol (Po0.01). Homeostasis model assessment (HOMA) score was positively related to the levels of MCP-1 (Po0.02) or IL-8 (Po0.03) in obese subject. Discussion: Our data demonstrated that the circulating levels of MCP-1 and IL-8 are related to obesity-related parameters such as BMI, waist circumference, CRP, IL-6, HOMA and HDL-cholesterol. These findings suggest that the circulating MCP-1 and/or IL-8 may be a potential candidate linking obesity with obesity-related metabolic complications such as atherosclerosis and diabetes.

YU, RINA, CHU-SOOK KIM, BYUNG-SE KWON, AND TERUO KAWADA. Mesenteric adipose tissue-derived monocyte chemoattractant protein-1 plays a crucial role in adipose tissue macrophage migration and activation in obese mice. Obesity. 2006;14:1353-1362. Objective: To determine whether chemokines, which play a pivotal role in monocyte/macrophage trafficking, modulate macrophage infiltration into and activation in the adipose tissues. Research Methods and Procedures: Various types of adipose tissue were isolated from different fat depots (e.g., mesenteric, epididymal, renal, and subcutaneous adipose tissues) from obese mice fed a high-fat diet and from non-obese controls fed a standard diet. The isolated tissues were cultured for 24, 48, and 72 hours. The level of monocyte chemoattractant protein-1 (MCP-1) expression and the amount of protein released were measured by reverse transcriptase-polymerase chain reaction or enzymelinked immunosorbent assay, respectively. Chemotaxis assay was performed to measure the degree of macrophage migration. Macrophage activation was estimated by measuring the concentrations of nitric oxide and tumor necrosis factor ␣. Results: The level of MCP-1 mRNA expression, protein content, and the amount of protein released significantly increased in the adipose tissues from the obese mice compared with those from the non-obese mice. The mesenteric adipose tissue produced the highest levels of MCP-1 protein among the four different fat depots. Mesenteric adipose tissue-conditioned medium induced the highest degree of macrophage migration and strongly induced macrophages to produce proinflammatory mediators such as nitric oxide and tumor necrosis factor ␣. The neutralization of MCP-1 in the adipose tissue-conditioned medium significantly inhibited the migration and activation of macrophages. Discussion: Our findings suggest that MCP-1 plays a crucial role in adipose tissue inflammatory response by activating and inducing the infiltration of macrophages into adipose tissues. MCP-1 may be closely associated with visceral obesity-related complications and, thus, may be a useful therapeutic target for modulating visceral obesityrelated diseases.

objective: A high intake of fat in the diet plays a crucial role in promoting obesity and obesity-related pathologies, and especially visceral obesity is closely associated with obesity-related complications. Because adipose tissue is anatomically associated with lymph nodes, the secondary lymphoid organ, we hypothesized that fat tissue-derived factors may influence the cellularity of lymphoid tissue embedded in fat. Methods and Procedures: Mesenteric and inguinal lymph nodes were isolated from obese mice fed a high-fat diet and control mice fed a regular diet. T-cell population, activation state, and the extent of apoptosis were determined by flow cytometric analysis or terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay. Results: The weight of mesenteric lymph nodes and the total number of lymphoid cells in the obese mice significantly decreased compared with those in the control mice; however, no change was observed in the weight of inguinal lymph nodes. The numbers of CD4 + and CD8 + T cells in the mesenteric lymph nodes of obese mice significantly decreased compared with those of the control. Enhanced T-cell activation and apoptosis were observed in the mesenteric lymph node cells of the obese mice. The treatment of lymph node cells with free fatty acids, oxidative stress, and chylomicrons, which are obesity-related factors, resulted in lymph node T-cell activation and apoptosis. Discussion: These results suggest that visceral fat accumulation with a high-fat diet can cause the atrophy of mesenteric lymph nodes by enhancing activation-induced lymphoid cell apoptosis. Dietary fat-induced visceral obesity may be crucial for obesity-related immune dysfunction.

Background The progressive fibrosing (PF) phenotype of interstitial lung disease (ILD) is characterised by worsening respiratory symptoms, lung function, and extent of fibrosis on high-resolution computed tomography. We aimed to investigate the prevalence and clinical outcomes of PF-ILD in a real-world cohort and assess the prognostic significance of the PF-ILD diagnostic criteria. Methods Clinical data of patients with fibrosing ILD other than idiopathic pulmonary fibrosis (IPF) consecutively diagnosed at a single centre were retrospectively reviewed. A PF phenotype was defined based on the criteria used in the INBUILD trial. Results The median follow-up duration was 62.7 months. Of the total of 396 patients, the mean age was 58.1 years, 39.9% were men, and rheumatoid arthritis-ILD was the most common (42.4%). A PF phenotype was identified in 135 patients (34.1%). The PF-ILD group showed lower forced vital capacity and total lung capacity (TLC) than the non-PF-ILD group. The PF-ILD group also showed poorer survival (median survival, 91.2 months vs. not reached; P < 0.001) than the non-PF-ILD group. In multivariable Cox analysis adjusted for age, DLCO, HRCT pattern, and specific diagnosis, PF phenotype was independent prognostic factor (hazard ratio, 3.053; P < 0.001) in patients with fibrosing ILD. Each criterion of PF-ILD showed similar survival outcomes. Conclusions Our results showed that approximately 34% of patients with non-IPF fibrosing ILD showed a progressive phenotype and a poor outcome similar to that of IPF, regardless of the diagnostic criteria used.

Adipocytes not only store energy, but also secrete biologically active molecules called adipocytokines, which play a pivotal role in adipocyte-related pathological processes such as diabetes and cardiovascular disease. Recent studies have shown that preadipocyte/adipocyte expresses chemokines (e.g. monocyte chemoattractant protein-1, macrophage in£ammatory protein-1 alpha) which alter adipocyte function, indicating the involvement of chemokines in adipocyte-related pathologies. The current study investigated the potential of macrophage in£am-matory protein-related protein-2 (MRP-2), a novel CC chemokine, to modulate preadipocyte tra⁄cking and adipocyte di¡er-entiation. MRP-2 and its receptors were highly expressed in preadipocytes and di¡erentiated adipocytes as well as in the mouse fat pad. Chemotaxis assays revealed that MRP-2 was a speci¢c chemotactic regulator in preadipocyte migration. The levels of MRP-2 expression in adipose tissue were enhanced in obese mice compared to lean mice. MRP-2 secretion by preadipocytes was suppressed during di¡erentiation. MRP-2 suppressed the expression of adipocyte di¡erentiation markers such as adipocyte fatty acid-binding protein and glycerol-3 phosphate dehydrogenase. Taken together, our data suggest that MRP-2 plays a role in the regulation of preadipocyte migration and adipocyte di¡erentiation during adipose tissue development. MRP-2 may be another adipocytokine, which can be involved in the adipocyte-related pathological process. ß

IntroductionDespite the significant disease burden of bronchiectasis in Korea, no large-scale, representative prospective cohort studies have been conducted to evaluate the clinical characteristics of Korean patients with bronchiectasis, indicating an urgent need for cohort studies on bronchiectasis.Methods and analysisThe Korean Multicenter Bronchiectasis Audit and Research Collaboration (KMBARC) is a prospective, non-interventional observational cohort study on bronchiectasis in Korea. The inclusion criteria of this registry are as follows: (1) adult patients (aged ≥18 years) with or without respiratory symptoms (cough, chronic sputum and/or recurrent respiratory infection) and chest computed tomography revealing bronchiectasis affecting one or more lobes and (2) stable status at the time of registration: patients with bronchiectasis who were admitted for a respiratory aetiology can be enrolled at least 4 weeks after hospital discharge. The exclusion criteria are as follows: (1) bronchiectasis due to cystic fibrosis; (2) traction bronchiectasis associated with interstitial lung disease; (3) patients actively being treated for pneumonia, pulmonary tuberculosis or non-tuberculous mycobacterial infection; (4) patients who are unable or unwilling to provide informed consent; and (5) pregnant patients. Although the KMBARC questionnaires for baseline and annual follow-up data are similar to the European Multicentre Bronchiectasis Audit and Research Collaboration questionnaires, KMBARC has distinctive features such as use of Bronchiectasis Health Questionnaires, measurement with fatigue and depression scales, blood tests, use of consensus definition of exacerbations and information on emergency room or hospitalisation.We aim to recruit at least 1200 patients over the study period from more than 26 hospitals in South Korea. Patients will undergo a detailed baseline and yearly assessment for up to 5 years. The study objectives of the KMBARC registry are as follows: (1) uncovering the natural course of bronchiectasis; (2) aiding in establishing evidence-based bronchiectasis guidelines in Korea; and (3) encouraging and facilitating studies on bronchiectasis in Korea.Ethics and disseminationThis study received necessary approval from the Institutional Review Boards of all participating institutions. The Asan Medical Center Institutional Review Board gave overall approval for the study. Results will be disseminated via peer-reviewed publications and conference presentations.Trial registration numberKCT0003088.

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Aims: Rifampicin is a key drug for the treatment of tuberculosis (TB). Little is known for the relationship between the rifampicin pharmacokinetics and genetic polymorphisms in the Asian population. We aimed to investigate relationship between genetic polymorphism of SLCO1B1 and rifampicin exposure and its impact on clinical outcomes in Korean patients with active pulmonary TB.Methods: From February 2016 to December 2019, patients with active pulmonary TB who were taking rifampicin for >1 week were prospectively enrolled. Serial or 1-time blood sampling was conducted to determine rifampicin concentrations. The genotype of 4 single nucleotide polymorphisms of SLCO1B1 was determined. To estimate the drug clearance and exposure, population pharmacokinetics analysis was conducted. Clinical outcomes such as time to acid-fast bacteria culture conversion, chest radiograph score changes from baseline, and all-cause mortality were also evaluated. The exposure among different SLCO1B1 genotype was compared and relationship between drug exposure and clinical outcomes were explored.Results: A total of 105 patients (70 males and 35 females) were included in the final analysis. The mean age of patients was 55.4 years. The mean drug clearance and exposure were 13.6 L/h and 57.9 mg h/L, respectively. The genetic polymorphisms of SLCO1B1 were not related to rifampicin clearance or exposure. As the rifampicin exposure increased, the chest radiographs improved significantly, but the duration of acid-fast bacteria culture conversion was not related to the drug exposure.Conclusion: SLCO1B1 gene polymorphisms did not influence rifampicin concentrations and clinical outcomes in Korean patients with active pulmonary TB.