Chi-Huei Chiang

BACKGROUND: The mechanism between ventilator-induced lung injury (VILI) and multiple organ injury is unclear. The aim of our study was to investigate the mechanisms of VILI-induced distal organ injury. METHODS: VILI was induced in rat lungs with high tidal volume (V _T ) ventilation of 40 mL/kg for 6 h. Rats with low V _T ventilation of 6 mL/kg served as controls. Inflammatory and apoptotic indices in lung and distal organs were assessed. RESULTS: VILI increased lung weight, airway pressure, inflammation, and apoptotic pathologic changes without hemodynamic changes. The white blood cell count and the levels of H ₂ O ₂ , interleukin-1β (IL-1β), tumor necrosis factor alpha, and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid were higher in the VILI group compared with the control group. H ₂ O ₂ , IL-1β, and tumor necrosis factor alpha in blood from the left ventricle were up-regulated. H ₂ O ₂ , IL-1β, tumor necrosis factor alpha, macrophage inflammatory protein-2, c-Jun N-terminal kinase, p38, nuclear factor kappa B, and caspase-3 in lung, heart, liver, and kidney tissues in the VILI group were up-regulated. Furthermore, the apoptotic score for the kidneys was higher than those for other distal organs in the VILI group. CONCLUSIONS: High V _T ventilation induces VILI and is associated with inflammation and apoptosis in distal organs. Up-regulation of reactive oxygen species and cytokines in VILI is associated with systemic inflammatory responses. Kidney tissue appears to be more vulnerable than heart and liver tissues following VILI.

Whether guideline-oriented pharmacotherapy prevents the decline in pulmonary function or reduces systemic inflammation associated with chronic obstructive pulmonary disease (COPD) is uncertain. The aim of this study was to assess the outcome of COPD in clinical practice under real-world conditions in Taiwan as measured by pulmonary function and systemic inflammation parameters (C-reactive protein (CRP) or white blood cell (WBC)) after initiation of guideline-oriented pharmacotherapy. Newly diagnosed COPD patients were enrolled and prospectively observed in real-world outpatient practice following initiation of pharmacotherapy of COPD. Pulmonary function, WBC and neutrophil counts, and CRP level of COPD patients were assessed annually. This study enrolled 566 patients and 263 returned for follow-up visits. Significantly higher postbronchodilator FVC, FEV₁, and FEV₁/FVC but lower DLCO were found at 1 year compared to baseline values. During 4-year follow-up period, FVC and FEV₁ remained stable. DLCO progressively declined compared to baseline. No significant changes were seen in CRP and neutrophil count over a 3-year period. Values of CRP, WBC, and neutrophil count correlated inversely with FEV₁, FVC, FEV₁/FVC, and DLCO. Guideline-oriented pharmacotherapy of COPD improves airflow limitation but does not prevent the alveolar destruction and systemic inflammation under real-world conditions in Taiwan. Es ist ungewiss, ob eine Leitlinien-orientierte Pharmakotherapie die Verschlechterung der Lungenfunktion bei einer chronisch obstruktiven Lungenerkrankung (COPD) verhindern kann, beziehungsweise ob die chronische Entzündung, die mit dieser Erkrankung einhergeht, dadurch reduziert wird. Ziel der Studie war es, den Verlauf der COPD in der klinischen Realität in Taiwan, gemessen durch Prüfung der Lungenfunktion und Parameter der systemischen Entzündung (C-reaktives Protein (CRP); oder weißes Blutbild (WBC)), nach Einsatz einer Leitlinien-orientierten Pharmakotherapie zu erfassen. Frisch diagnostizierte COPD Patienten wurden in die Studie aufgenommen und prospektiv unter Bedingungen der klinischen Realität im ambulanten Bereich nach Beginn einer Pharmakotherapie der COPD beobachtet. Lungenfunktion und WBC mit Differential Blutbild wurden jährlich erhoben. Von den 566 in die Studie aufgenommenen Patienten kamen 263 zu den Kontrolluntersuchungen. Im Vergleich zu den Vorwerten waren die post-bronchodilatorische FVC, FEV₁ und FEV₁/FVC 1 Jahr später signifikant höher, die DLCO Werte jedoch signifkant niedriger. Nach 4 Jahren blieben die FVC und FEV₁ Werte stabil, die DLCO kehrten langsam zu den Ausgangswerten zurück. Die CRP Werte und das WBC unterschieden sich 3 Jahre nach Therapiebeginn nicht signifikant von den Werten vor Therapie. CRP, WBC und die Zahl der Neutrophilen korrelierten mit FEV₁, FVC, FEV₁/FVC und DLCO invers. Unter Bedingungen der klinischen Realität in Taiwan verbessert eine Leitlinien orientierte Pharmakotherapie der COPD zwar die Einschränkung des Atemflusses, schützt aber nicht vor der alveolären Destruktion beziehungsweise der systemischen Entzündung.

The association between genetic polymorphisms of ADRβ2, IL-4, and ADAM3 and asthma remains undetermined. Furthermore, it is not clear as to whether these three gene polymorphisms combined produce a correlative increase in asthmatic risk. A total of 476 asthmatic patients and 115 healthy volunteers were enrolled. Single nucleotide polymorphisms (SNPs) of the C-589T IL-4 promoter (rs2243250), the ADRβ2 gene [at nucleic acid 46 (rs1042713) and 79 (rs1042714)] and the ADAM33 gene [at rs2280091 (T1), rs3918396 (S1), rs3918391 (D1), and rs615436] were analyzed. Pulmonary function tests, methacholine challenge tests, total IgE, specific IgE for inhalant allergens and total eosinophil counts were assessed. The T allele for the IL-4 gene promoter (C-589T locus), the C allele frequency for ADRβ2 (Gln27Glu locus), and the A allele for the ADAM33 gene (rs2280091, T1) were higher in asthma patients than in normal individuals. In asthmatic patients, the A allele of ADAM33 (rs2280091) was associated with higher eosinophil count and increased hyperresponsiveness compared to the C allele. Combination of the three risk genes SNP had an additive effect on the risk of asthma (OR: 3.46; CI: 1.51-7.93) and increased the diagnostic sensitivity and specificity of asthma. Genetic polymorphism in the IL-4 promoter, ADRβ2, and ADAM33 is associated with asthma. Furthermore, ADAM33 genetic polymorphism modifies the phenotype of asthma in atopy and hyperresponsiveness. Asthma is a complex polygenic disease, and combinations of polymorphisms of various genes have an additive effect on the risk of asthma.

Background and objective:  The prevalence of COPD in the Western Pacific is increasing. The present study determined the total direct health‐care costs for the management of COPD patients with differing degrees of disease severity. The study also aimed to find the key cost drivers in the management of COPD.Methods:  COPD patients were recruited from a tertiary care hospital during April 2002 and March 2003. One‐year costs were identified by applying cost data to medical information obtained by review of medical records. Costs included those for medications, oxygen therapy, laboratory and diagnostic tests, clinic visits, emergency room visits and hospital stays.Results:  There were 160 patients recruited. Patients were categorized by COPD severity: moderate A COPD (50 ≤ FEV₁% < 80; n = 54), moderate B COPD (30 ≤ FEV₁% < 50; n = 54) and severe COPD (FEV₁% < 30; n = 52). Patients with moderate A, moderate B and severe COPD had an average of 0.82, 2.6 and 3.5 exacerbations per year, respectively. Average numbers of emergency room visits were 0.41 ± 0.94, 1.20 ± 1.39 and 1.73 ± 2.44 per year in moderate A, moderate B and severe COPD patients, respectively. The mean total direct costs were New Taiwan dollars 288 825, 149 031 and 38 203 for severe COPD, moderate B COPD and moderate A COPD, respectively. The total annual cost was correlated with the disease severity. Hospitalization contributed the major portion of cost and also correlated with disease severity.Conclusions:  There is a correlation between the cost of COPD and disease severity with hospitalization owing to disease exacerbation being a major contributor to cost. The keys to reducing health‐care costs lie with reducing the frequency of exacerbations and the disease severity.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), which manifests as non-cardiogenic pulmonary edema, respiratory distress and hypoxemia, could be resulted from various processes that directly or indirectly injure the lung. Extensive investigations in experimental models and humans with ALI/ARDS have revealed many molecular mechanisms that offer therapeutic opportunities for cell or gene therapy. Herein the present strategies and future perspectives of the treatment for ALI/ARDS, include the ventilatory, pharmacological, as well as cell therapies.

Background and objectives:  Recent family‐based studies have revealed a linkage between human chromosome 5q31 and asthma, elevated serum IgE levels and airway hyperresponsiveness (AHR). Among the candidate genes in this region is the gene encoding IL‐4. This gene could be a candidate gene for asthma. The aim of this prospective case‐control study was to assess the frequency of polymorphisms in the IL‐4 gene promoter among asthmatic patients from Taiwan.Methods:  The study consisted of 167 patients with asthma and 111 healthy subjects. PCR amplification followed by Bsm F1 restriction digestion were used to assign genotypes at the IL‐4 promoter C‐589T locus. Pulmonary function tests, methacholine challenge tests, total IgE, specific IgE antibodies against common inhalant allergens and total eosinophil counts were assessed in asthmatic patients.Results:  The T allele frequency for the C‐589T IL‐4 gene promoter in asthma patients was higher than for normal subjects (P < 0.0001). The frequency discrepancy was found to be even higher for asthmatic patients with severe AHR (P < 0.05). There were no significant differences for the T allele frequency among asthmatic patients with the various other phenotypes such as high versus normal total eosinophil, high versus normal total IgE and high versus normal levels of specific IgE against mite, cockroach or cat dander, or dog dander.Conclusions:  Polymorphism in the promoter of the IL‐4 gene is associated with asthma and is a disease modifier in terms of the severity of AHR.

Inhibition of neutrophil activation and adherence to endothelium by antibodies to tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecules (ICAM-1), respectively, might attenuate ischemia-reperfusion injury (I/R). I/R was conducted in an isolated rat lung model. Anti-TNF-alpha antibody and/or anti-ICAM-1 antibody were added before ischemia or after reperfusion. Hemodynamic changes, lung weight gain (LWG), capillary filtration coefficients (Kfc), and pathologic changes were assessed to evaluate the severity of I/R. The LWG, Kfc, pathological changes and lung injury score of treatment groups with anti-TNF-alpha antibody treatment, either pre-ischemia or during reperfusion, were less than those observed in control groups. Similar findings were found in group treated with anti-ICAM-1 antibody or combination therapy during reperfusion. In contrast, pre-I/R treatment with anti-ICAM-1 antibody induced severe lung edema and failure to complete the experimental procedure. No additional therapeutic effect was found in combination therapy. We conclude that TNF-alpha and ICAM-1 play important roles in I/R. Anti-TNF-alpha antibody has therapeutic and preventive effects on I/R. However, combined therapy with anti-TNF-alpha antibody and anti-ICAM-1 antibody may have no additive effect and need further investigation.

Background: Asthma has rarely been studied by evaluating all of its trigger factors in 1 study population. Thus, correlations between the concentration of allergen immunoglobulin (Ig) E antibodies and airway limitation or asthma severity remain unclear. Methods: Five hundred and seventy-nine asthmatic patients were enrolled, and serum specific IgE antibodies to allergens were analyzed. All suspected trigger factors were assessed by questionnaire, case histories over a 4-year period, and diary card recordings; possible trigger factors were then re-evaluated. Results: Antibodies to the following allergens were found: Dermatophagoides pteronyssinus (59.8% of patients), D. microceras (58.8%), D. farinae (56.8%), cockroach (38.3%), dog dander (26.3%), Candida albicans (13.3%), cat dander (10%), and Cladosporium herbarum (6.6%). A greater prevalence of allergy to dog and cat dander was found than previously. Younger patients were more often positive for mite allergens, and had higher titers of antibodies against such allergens, than older patients. Further, females had a lower concentration of mite allergen antibodies than males. No correlation between the concentration of allergen antibodies and forced expiratory volume in 1 second (FEV₁), or the ratio of FEV₁:forced vital capacity (FEV₁:FVC), was found. In addition, there was no significant change in antibody titers with varying asthma severity. Non-allergenic trigger factors were irritant air inhalants (94.6% of patients), respiratory infection (92.2%), exercise (75.2%), emotional factors (58.8%), drugs and chemical substances (16%). Conclusion: There are multiple trigger factors in asthma. Allergenic trigger factors are more common in younger than older patients, whereas non-allergenic trigger factors are more common in older patients. There was no linear correlation between the concentration of specific IgE antibodies and asthma severity or airway limitation; therefore, to prevent asthma attacks in individual asthmatic patients, greater attention should be paid to avoiding all potential trigger factors, and not just house dust mite allergens.