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Alcoholic lung injury: Metabolic, biochemical and immunological aspects.

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Alcoholic lung injury: Metabolic, biochemical and immunological aspects.

Toxicol Lett. 2013 Jul 24;

Authors: Kaphalia L, Calhoun WJ

Abstract
Chronic alcohol abuse is a systemic disorder and a risk factor for acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). A significant amount of ingested alcohol reaches airway passages in the lungs and can be metabolized via oxidative and non-oxidative pathways. About 90% of the ingested alcohol is metabolized via hepatic alcohol dehydrogenase (ADH)-catalyzed oxidative pathway. Alcohol can also be metabolized by cytochrome P450 2E1 (CYP2E1), particularly during chronic alcohol abuse. Both the oxidative pathways, however, are associated with oxidative stress due to the formation of acetaldehyde and/or reactive oxygen species (ROS). Alcohol ingestion is also known to cause endoplasmic reticulum (ER) stress, which can be mediated by oxidative and/or non-oxidative metabolites of ethanol. An acute as well as chronic alcohol ingestions impair protective antioxidants, oxidize reduced glutathione (GSH, cellular antioxidant against ROS and oxidative stress), and suppress innate and adaptive immunity in the lungs. Oxidative stress and suppressed immunity in the lungs of chronic alcohol abusers collectively are considered to be major risk factors for infection and development of pneumonia, and such diseases as ARDS and COPD. Prior human and experimental studies attempted to identify common mechanisms by which alcohol abuse directly causes toxicity to alveolar epithelium and respiratory tract, particularly lungs. In this review, the metabolic basis of lung injury, oxidative and ER stress and immunosuppression in experimental models and alcoholic patients, as well as potential immunomodulatory therapeutic strategies for improving host defenses against alcohol-induced pulmonary infections are discussed.

PMID: 23892124 [PubMed - as supplied by publisher]

Nutrition disorder and systemic inflammation in patients with chronic obstructive pulmonary disease.

Aim : To detect nutrition disorders (underweight and obesity) in patients with chronic obstructive disease (COPD) and presence of systemic inflammation by determination of inflammatory mediators serum values C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α) and leptin.

Methods : The examination involved 85 patients with COPD. Nutrition categories were defined by body mass index (BMI). Fat free mass (FFM) was evaluated by mid upper-arm circumference (MUAC) and fat mass (FM) by tricipital skin-fold thickness (TFS). Values of TNF-α and leptin were measured by standardized ELISA kits and, CRP by latex turbidimetry.

Results : There were 14 (16.5%) underweight patients, 28 (32.9%) normal, 28 (32.9%) pre-obese and 15 (17.6%) obese. Values of MUAC and TSF were significantly different among the nutrition categories (p=0.000). The lowest MUAC and TSF values were in the underweight, and the highest in the obese. There was no significant difference of CRP and TNF-α among nutrition categories. Leptin of the underweight and normal nutrition was significantly different from leptin of the pre-obese and obese (p=0.000). The highest CRP and the lowest TNF-α and leptin were in the underweight patients. The obese had the lowest CRP (although increased as compared to normal values) and the highest leptin, while the pre-obese had the highest TNF-α.

Conclusion : Two basic nutrition disorders (underweight and obesity) were manifested in COPD patients. The inflammatory profile differs between underweight COPD patients and obese. Probably that happens due to systemic inflammation, and in part due to dysfunction of adipose tissue. Key words: chronic airflow obstruction, nutrition assessment, Creactive protein, tumor necrosis factor-alpha, leptin.

Increased DNA Damage in Progression Of COPD: A Response By Poly(ADP-Ribose) Polymerase-1.

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Chronic oxidative stress (OS), a major mechanism of chronic obstructive pulmonary disease (COPD), may cause significant damage to DNA. Poly(ADP-ribose) polymerase (PARP)-1 is rapidly activated by OS-induced DNA lesions. However, the degree of DNA damage along with the evolution of COPD is unclear.

In peripheral blood mononuclear cells of non-smoking individuals, non-obstructive smokers, patients with COPD of all stages and those with COPD exacerbation, we evaluated DNA damage, PARP activity and PARP-1 mRNA expression using Comet Assay IV, biotinylated-NAD incorporation assay and qRT-PCR, respectively and subjected results to ordinal logistic regression modelling.

Adjusted for demographics, smoking-related parameters and lung function, novel comet parameters, tail length/cell length ratio and tail migration/cell length ratio, showed the greatest increase along the study groups corresponding to the evolution of COPD [odds ratio (OR) 7.88, 95% CI 4.26-14.57; p<0.001 and OR 3.91, 95% CI 2.69-5.66; p<0.001, respectively]. Analogously, PARP activity increased significantly over the groups (OR = 1.01; 95%; p<0.001). An antioxidant tetrapeptide UPF17 significantly reduced the PARP-1 mRNA expression in COPD, compared to that in non-obstructive individuals (p = 0.040).

Tail length/cell length and tail migration/cell length ratios provide novel progression-sensitive tools for assessment of DNA damage. However, it remains to be elucidated whether inhibition of an elevated PARP-1 activity has a safe enough potential to break the vicious cycle of the development and progression of COPD.

Evaluation of salmeterol xinafoate plus fluticasone propionate for the treatment of chronic obstructive pulmonary disease.

Current clinical guidelines recommend long-acting bronchodilators as the mainstay of the pharmacotherapy of patients with chronic obstructive pulmonary disease (COPD). Inhaled corticosteroids (ICS), in conjunction with long-acting beta-agonists (LABA), are routinely considered at severe and very severe stages of COPD when patients lack adequate response to single-therapy with LABAs. Although the study methodologies evaluating the clinical effectiveness of the combination therapy using salmeterol and fluticasone (SAL/FLU) for patients with COPD have been questioned, a number of studies have suggested that using ICS, in combination with a LABA agent, may improve survival of patients with COPD.

Areas covered: This article attempts to review the most current evidence for using SAL/FLU in the management of COPD and summarizes the results of outcome measures reported in randomized controlled trials.

Expert opinion: Until new forms of drug combinations are made available, the use of dual-therapy containing a LABA and ICS remain as the most logical and appropriate approach for the treatment of patients suffering from severe and very severe COPD with repeated exacerbations.

Factors associated with change in exacerbation frequency in COPD.

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Patients with chronic obstructive pulmonary disease (COPD) can be categorized as having frequent (FE) or infrequent (IE) exacerbations depending on whether they respectively experience two or more, or one or zero exacerbations per year. Although most patients do not change category from year to year, some will, and the factors associated with this behaviour have not been examined.

METHODS: 1832 patients completing two year follow-up in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study were examined at baseline and then yearly. Exacerbations were defined by health care utilisation. Patient characteristics compared between those patients who did or did not change exacerbation category from year 1 to year 2.

FINDINGS: Between years 1 and 2, 221 patients (17%) changed from IE to FE and 210 patients (39%) from FE to IE. More severe disease was associated with changing from IE to FE and less severe disease from FE to IE. Over the preceding year, small falls in FEV1 and 6-minute walking distance were associated with changing from IE to FE, and small falls in platelet count associated with changing from FE to IE.

CONCLUSION: No parameter clearly predicts an imminent change in exacerbation frequency category.Trial registration: SCO104960, clinicaltrials.gov identifier NCT00292552.

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