Chin Kook Rhee

Blockade of IL-33/ST2 ameliorates airway inflammation in a murine model of allergic asthma

ABSTRACT Objective: Interleukin (IL)-33 is involved in the development of lung inflammation by inducing or amplifying Th2 type-mediated responses in various animal models of allergic asthma. The ST2 gene is a member of the IL-1 receptor family, producing a transmembrane form (ST2L) and a soluble secreted form (sST2). sST2 has been shown to block this IL-33/ST2 signaling pathway. This study aimed to investigate whether anti-IL-33 and sST2 reduced airway inflammation in a murine model of asthma. Methods: BALB/c mice were sensitized and challenged with ovalbumin (OVA), and the effect of sST2 and anti-IL-33 antibody on airway inflammation and airway hyperresponsiveness (AHR) was evaluated. Furthermore, we measured changes in various cytokines in the bronchoalveolar lavage (BAL) fluid when treated with sST2 or anti-IL-33. Results: We observed that anti-IL-33 antibody and sST2 exert a negative regulation on OVA-mediated allergic airway inflammation. Both treatments reduced total cell counts and eosinophil counts in BAL fluid and AHR to methacholine. The Th2 cytokines, such as IL-4, IL-5, and IL-13 in BAL fluid were also significantly decreased after both treatments. However, there were no changes in the level of TGF- ß1 and IL-10 after each treatment. Conclusions: These results suggest that anti-IL-33 as well as sST2 have therapeutic potential for allergic asthma through inhibition of Th2 cytokine production.

Medical utilization and cost in patients with overlap syndrome of chronic obstructive pulmonary disease and asthma.

Abstract Background: Little information is available regarding medical utilization and cost in patients with overlap syndrome of chronic obstructive pulmonary disease (COPD) and asthma. The purpose of this study is to analyze medical utilization and cost in patients with overlap syndrome and to compare them to COPD patients without asthma. Methods: Using the 2009 Korean National Health Insurance (NHI) database, COPD patients were identified. Medical utilization and costs were also analyzed. Results: Of a total of 185,147 patients identified with COPD, 101,004 patients were classified with overlap syndrome of COPD and asthma and 84,143 patients with COPD without asthma. In 2009, the percentages of emergency room visits, admissions, and intensive care unit admissions were 14.6%, 30.5%, and 0.5%, respectively, in the patients with overlap syndrome group and 5.0%, 14.1%, and 0.2%, respectively, in the COPD patients without asthma group (p < 0.05 for all comparisons). The cost of medical utilization was 790 ± 71 US dollars per person and 3,373 ± 4,628 dollars per person for outpatient and inpatient services, respectively, in the patients with overlap syndrome and 413 ± 512 and 3,010 ± 5,013, respectively, in the COPD patients without asthma (p < 0.05 for all comparisons). Multiple linear regression showed that age, sex, overlap syndrome, hospitalization in the last year, low socioeconomic status, and type of hospital use were significant factors affecting medical utilization and cost. Conclusions: In patients with overlap syndrome, both medical utilization and cost were higher than in COPD patients without asthma.

Clinical Characteristics and Corticosteroid Treatment of Acute Eosinophilic Pneumonia

The clinical characteristics and optimal duration of corticosteroid treatment for acute eosinophilic pneumonia (AEP) have not been fully evaluated. This was a retrospective study of prospectively collected data from 137 patients with AEP, treated with standardised protocol, to clarify the clinical characteristics and compare the efficacies of 2 weeks versus 4 weeks of corticosteroid treatment for AEP. The majority of the patients altered their smoking habits within a median (interquartile range) of 17 (13–26) days prior to development of AEP. 80 (58%) patients presented with acute respiratory failure. A total of 127 (92%) patients were treated with corticosteroids: 4 weeks, n=42; 2 weeks, n=85. Major symptoms were resolved in 3 days and the severity of respiratory failure was inversely correlated with clinical outcomes. After adjusting for differences in baseline characteristics between the groups, the differences in adjusted mean (95% confidence interval) for resolution of dyspnoea and disappearance of all symptoms were 0.57 (-0.71–1.86) and -0.04 (-1.91–1.83) days, respectively. The difference in adjusted proportion of resolution of radiological abnormalities was 6.92% (-8.19–22.02). In conclusion, the duration of corticosteroid treatment could be shortened to 2 weeks, even in patients with respiratory failure.

Effect of Nilotinib on Bleomycin-Induced Acute Lung Injury and Pulmonary Fibrosis in Mice

Background: The tyrosine kinase inhibitor imatinib mesylate was developed as an inhibitor of the kinase activity of BCR-ABL. However, imatinib also has potent inhibitory activity against the platelet-derived growth factor receptor (PDGFR). Nilotinib is approved for treating patients with chronic myeloid leukemia showing resistance or intolerance to imatinib. Like imatinib, nilotinib selectively inhibits the tyrosine kinase activity of PDGFR. Objectives: We examined the effect of imatinib and nilotinib on acute lung injury and pulmonary fibrosis in a mouse model. Methods: Mice were treated by intratracheal instillation of bleomycin. Imatinib or nilotinib were administered by oral gavage. To study the early inflammatory and late fibrotic phases of lung injury, mice were sacrificed on days 3, 7, 14 and 21 after bleomycin instillation. Results: Histopathology showed that imatinib and nilotinib attenuated the extent of lung injury and fibrosis. The numbers of inflammatory cells and levels of IL-6, IL-1β and tumor necrosis factor-α were decreased in the imatinib and nilotinib groups on days 3 and 7. Imatinib and nilotinib therapy significantly reduced the levels of hydroxyproline on days 14 and 21, which was accompanied by decreased expression levels of transforming growth factor (TGF)-β1 and PDGFR-β. Imatinib and nilotinib also significantly reduced the expression levels of the genes for TGF-β1 and platelet-derived growth factor (PDGF). Imatinib and nilotinib treatment also significantly inhibited the PDGF-induced proliferation of lung fibroblasts in vitro. When imatinib or nilotinib was given 7 days after the instillation of bleomycin, only nilotinib attenuated pulmonary fibrosis. Conclusions: Imatinib and nilotinib attenuated bleomycin-induced acute lung injury and pulmonary fibrosis in mice. In a therapeutic model, nilotinib showed more potent antifibrotic effects than imatinib.

Effect of Imatinib on Airway Smooth Muscle Thickening in a Murine Model of Chronic Asthma

Background: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and remodeling. The tyrosine kinase inhibitor imatinib mesylate was developed to inhibit BCR-ABL kinase activity; however, it also has potent inhibitory activity against the c-Kit and platelet-derived growth factor receptors. The present study aimed to determine whether imatinib suppresses airway smooth muscle (ASM) remodeling and whether its effect is associated with growth factors such as transforming growth factor (TGF)-β1 and stem cell factor (SCF). Methods: We developed a mouse model of airway remodeling, which includes smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated with imatinib during the OVA challenge. Results: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and AHR compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of imatinib significantly inhibited the development of AHR, eosinophilic inflammation and, importantly, ASM remodeling in mice chronically exposed to OVA. Imatinib treatment significantly reduced the levels of interleukin-4, -5 and -13. In addition, TGF-β1 and SCF were significantly reduced in the imatinib-treated animals. Conclusions: These results suggest that imatinib administration can prevent not only airway inflammation, but also airway remodeling associated with chronic allergen challenge. Imatinib may provide a clinically attractive therapy for chronic severe asthma.

Effect of tiotropium bromide on airway remodeling in a chronic asthma model

BACKGROUND Recent evidence suggests that acetylcholine acting through muscarinic receptors may play an inhibitory role in the mechanisms that drive the structural changes in the airways called airway remodeling. The novel anticholinergic drug tiotropium bromide, which selectively antagonizes muscarinic receptors, especially the M3 subtype, and is long acting, could be beneficial in attenuating airway remodeling in chronic asthma. OBJECTIVE To investigate the effect of tiotropium bromide on parameters of airway remodeling, including smooth muscle hypertrophy and peribronchial thickening, in a mouse model of chronic asthma. METHODS To develop the murine models of acute and chronic asthma, BALB/c mice were sensitized and challenged to ovalbumin for 1 and 3 months, respectively. The effect of tiotropium bromide (0.1mM in 50 μL of phosphate-buffered saline) on pulmonary inflammation and remodeling was evaluated. The expression of muscarinic receptors M2 and M3 was analyzed. RESULTS In the chronic asthma model, the tiotropium-treated group significantly decreased smooth muscle thickening and peribronchial collagen deposition. As for pulmonary inflammation, the chronic asthma model had a reduction of inflammatory cells and T(H)2 cytokines by tiotropium bromide, but the effects in the asthma acute model were reversed. In the chronic asthma model, expression of the M3 receptor was inhibited and that of the M2 receptor was elevated by the administration of tiotropium bromide. CONCLUSION This study suggests that tiotropium bromide might have an inhibitory effect on airway remodeling in a murine model of chronic asthma. Differential effects on muscarinic receptor subtypes may explain why tiotropium bromide has different effects on acute and chronic asthma.

Feasibility of high-flow nasal cannula oxygen therapy for acute respiratory failure in patients with hematologic malignancies: A retrospective single-center study

PURPOSE This study investigated the feasibility of high-flow nasal cannula (HFNC) oxygen therapy for acute respiratory failure in adult patients with hematologic malignancies. MATERIALS AND METHODS We identified 45 acute respiratory failure patients with hematologic malignancies who received HFNC therapy between March 2012 and June 2014 at Seoul St Marys Hospital. Their medical records were reviewed retrospectively to identify useful prognostic factors for successful treatment. RESULTS Of the 45 patients, 15 (33.3%) successfully recovered, and 30 were changed to invasive ventilation due to failed HFNC treatment. The etiologies of acute respiratory failure were bacterial pneumonia (57.8%), Pneumocystis jirovecii pneumonia (17.8%), pulmonary edema (8.9%), and bronchiolitis obliterans organizing pneumonia (8.9%). The overall mortality rate was 62.2%. The HFNC treatment success rate was significantly different between the survivors and nonsurvivors. To evaluate risk factors for HFNC treatment failure, differences between the HFNC treatment success and failure groups were compared. There were no significant differences in the severity of underlying medical conditions. The percentage of bacterial pneumonia was significantly higher in the HFNC treatment failure group compared with the success group (73.3% vs 26.7%; P = .004). CONCLUSIONS High-flow nasal cannula offers an interesting alternative to invasive ventilation in acute respiratory failure patients with hematologic malignancies. However, attention must be paid to the appropriate choice of HFNC settings such as oxygen flow.

Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies.

IntroductionNeutropenia recovery may be associated with deterioration in oxygenation and exacerbation of pre-existing pulmonary disease. However, risk factors for acute respiratory distress syndrome (ARDS) during neutropenia recovery in patients with hematologic malignancies have not been studied.MethodsWe studied critically ill patients with hematologic malignancies with the dual objectives of describing patients with ARDS during neutropenia recovery and identifying risk factors for ARDS during neutropenia recovery. A cohort of consecutive neutropenic patients with hematologic malignancies who were admitted to the intensive care unit (ICU) was studied. During a 6-year period, 71 patients recovered from neutropenia, of whom 38 (53.5%) developed ARDS during recovery.ResultsCompared with non-ARDS patients, patients who experienced ARDS during neutropenia recovery were more likely to have pneumonia, be admitted to the ICU for respiratory failure, and receive mechanical ventilator therapy. The in-ICU mortality was significantly different between the two groups (86.8% versus 51.5%, respectively, for patients who developed ARDS during neutropenia recovery versus those who did not during neutropenia recovery). In multivariate analysis, only occurrence of pneumonia during the neutropenic episode was associated with a marked increase in the risk of ARDS (odds ratio, 4.76).ConclusionsPatients with hematologic malignancies complicated by pneumonia during neutropenia are at increased risk for ARDS during neutropenia recovery.

Detection and comparison of EGFR mutations in matched tumor tissues, cell blocks, pleural effusions, and sera from patients with NSCLC with malignant pleural effusion, by PNA clamping and direct sequencing

Peptide nucleic acid (PNA)-mediated real-time PCR clamping has higher sensitivity than conventional direct sequencing for detecting mutations. Pleural effusion and serum may provide good samples in which to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients. We studied 37 NSCLC patients with malignant pleural effusion. EGFR mutations were assessed by PNA clamping and direct sequencing using tumor tissues, cell blocks, pleural effusion, and serum. Concordance between PNA clamping and direct sequencing results, and the diagnostic performance of pleural effusion were investigated. The κ coefficients for the two methods were 0.68 (p = 0.0007), 0.91 (p < 0.0001), 0.75 (p < 0.0001) and -0.01 (p = 0.8639) for tissues, cell blocks, pleural effusion, and serum, respectively. The diagnostic performance of pleural effusion compared with the combination of tumor tissue and cell blocks showed 89% sensitivity, 100% specificity, positive predictive value of 100%, and negative predictive value of 95% by PNA clamping, and 67% sensitivity, 90% specificity, positive predictive value of 75%, and negative predictive value of 86% by directing sequencing. A patient in whom an EGFR mutation was identified in pleural effusion only by PNA clamping showed a significant response to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. In contrast to the limited role of serum samples, pleural effusion had a diagnostic performance for the detection of EGFR mutations in NSCLC that was comparable to that of tumor tissues and cell blocks. The diagnostic performance of PNA clamping was good compared with that of direct sequencing. A more sensitive and accurate detection of EGFR mutations would benefit patients by allowing a better prediction of the response to EGFR-TKI treatment.

Prognostic factors in critically ill patients with hematologic malignancies admitted to the intensive care unit.

OBJECTIVE Despite an improvement in the prognosis of patients with hematologic malignancies, the mortality of such patients transferred to the intensive care unit (ICU) is high. This study determined the predictors of mortality in a cohort of critically ill patients with hematologic malignancies admitted to the ICU. METHODS We studied 227 critically ill patients with hematologic malignancies who were admitted to the ICU between April 2009 and December 2011. A cohort of consecutive patients with hematologic malignancies was reviewed retrospectively to identify clinically useful prognostic factors. RESULTS The ICU mortality rate was 84.1%, and the in-hospital mortality rate was 89.9%. The ICU mortality was significantly higher in patients with acute leukemia than in those with other malignancies. A significant difference between survivors and nonsurvivors was found in neutropenia and its recovery during the ICU stay, presence of cardiac dysfunction, the need for an invasive mechanical ventilator, use of inotropic/vasopressor agents, platelet count, aspartate transaminase level, pH, and Acute Physiology And Chronic Health Evaluation II score. In the multivariate analysis, acute leukemia, need for invasive mechanical ventilator, use of inotropic/vasopressor agents, and Acute Physiology And Chronic Health Evaluation II scores were independently associated with a worse outcome in patients with hematologic malignancies admitted to the ICU. CONCLUSION Higher mortality in patients with hematologic malignancies admitted to the ICU is associated with more severe illness, as reflected by higher organ failure scores or respiratory or hemodynamic instability. Mortality is higher in patients with acute leukemia as compared with other hematologic malignancies.