The danger signal plus DNA damage 2-hit hypothesis for chronic inflammation in COPD.

Eur Respir J. 2013 Feb 8;

Authors: Aoshiba K, Tsuji T, Yamaguchi K, Itoh M, Nakamura H

Abstract
Inflammation in chronic obstructive pulmonary disease (COPD) is thought to originate from the activation of innate immunity by a danger signal (first hit), although this mechanism does not readily explain why the inflammation becomes chronic. Here, we propose a 2-hit hypothesis explaining why inflammation becomes chronic in patients with COPD. A severer degree of inflammation exists in the lungs of patients who develop COPD than in the lungs of healthy smokers, and large amounts of reactive oxygen species (ROS) and reactive nitrogen species (RNS) released from inflammatory cells likely induce DNA double-strand breaks (second hit) in the airways and pulmonary alveolar cells, causing apoptosis and cell senescence. The DNA damage response and senescence-associated secretory phenotype (SASP) are also likely activated, resulting in the production of pro-inflammatory cytokines. These pro-inflammatory cytokines further stimulate inflammatory cell infiltration, intensifying cell senescence and SASP through a positive-feedback mechanism. This vicious cycle, characterized by mutually reinforcing inflammation and DNA damage, may cause the inflammation in patients with COPD to become chronic. Our hypothesis helps explain why COPD tends to occur in the elderly, why the inflammation worsens progressively, why inflammation continues even after smoking cessation, and why COPD is associated with lung cancer.

PMID: 23397294 [PubMed - as supplied by publisher]

Efficacy of pulmonary rehabilitation in patients with moderate chronic obstructive pulmonary disease: a randomized controlled trial.

BMC Fam Pract. 2013 Feb 11;14(1):21

Authors: Román M, Larraz C, Gómez A, Ripoll J, Mir I, Miranda EZ, Macho A, Thomas V, Esteva M

Abstract
ABSTRACT: BACKGROUND: Pulmonary Rehabilitation for moderate Chronic Obstructive Pulmonary Disease in primary care could improve patients' quality of life. METHODS: This study aimed to assess the efficacy of a 3-month Pulmonary Rehabilitation (PR) program with a further 9 months of maintenance (RHBM group) compared with both PR for 3 months without further maintenance (RHB group) and usual care in improving the quality of life of patients with moderate COPD.We conducted a parallel-group, randomized clinical trial in Majorca primary health care in which 97 patients with moderate COPD were assigned to the 3 groups. Health outcomes were quality of life, exercise capacity, pulmonary function and exacerbations. RESULTS: We found statistically and clinically significant differences in the three groups at 3 months in the emotion dimension (0.53; 95%CI0.06-1.01) in the usual care group, (0.72; 95%CI0.26-1.18) the RHB group (0.87; 95%CI 0.44-1.30) and the RHBM group as well as in fatigue (0.47; 95%CI 0.17-0.78) in the RHBM group. After 1 year, these differences favored the long-term rehabilitation group in the domains of fatigue (0.56; 95%CI 0.22-0.91), mastery (0.79; 95%CI 0.03-1.55) and emotion (0.75; 95%CI 0.17-1.33). Between-group analysis only showed statistically and clinically significant differences between the RHB group and control group in the dyspnea dimension (0.79 95%CI 0.05-1.52). No differences were found for exacerbations, pulmonary function or exercise capacity. CONCLUSIONS: We found that patients with moderate COPD and low level of impairment did not show meaningful changes in QoL, exercise tolerance, pulmonary function or exacerbation after a one-year, community based rehabilitation program. However, long-term improvements in the emotional, fatigue and mastery dimensions (within intervention groups) were identified.Trial registration: ISRCTN94514482.

PMID: 23399113 [PubMed - as supplied by publisher]

Blocking of thromboxane A(2) receptor attenuates airway mucus hyperproduction induced by cigarette smoke.

Eur J Pharmacol. 2013 Feb 7;

Authors: An J, Li JQ, Wang T, Li XO, Guo LL, Wan C, Liao ZL, Dong JJ, Xu D, Wen FQ

Abstract
Cigarette smoking is one of the risk factors for chronic obstructive pulmonary disease (COPD). In this study, we investigated the effects of thromboxane A(2) (TxA(2)) receptor antagonists on airway mucus production induced by cigarette smoke. Rats were exposed to cigarette smoke 1h/day, 6 days/week for 4 weeks. Seratrodast (2, 5, 10mg/kg·day) was administered intragastrically prior to smoke exposure. Thromboxane B(2) (TxB(2)) in the bronchoalveolar lavage fluid and lung tissues was determined by enzyme immunoassay. Airway mucus production was determined by alcin-blue/periodic acid sthiff (AB-PAS) staining, Muc5ac immunohistochemical staining, and RT-PCR. The phosphorylation of ERK and p38 was evaluated by Western blotting. Seratrodast reduced the overproduction of TxB(2) in both bronchoalveolar lavage fluid and lung tissues. Cigarette smoke exposure markedly increased AB/PAS-stained goblet cells and rat Muc5ac expression in the airway, which was significantly attenuated by seratrodast administration. The induced phosphorylation of ERK and p38 was also attenuated by seratrodast. TxA(2) receptor antagonist could reduce Muc5ac production induced by cigarette smoke in vivo, possibly through the mitogen-activated protein kinases (MAPK) signaling pathway.

PMID: 23399768 [PubMed - as supplied by publisher]

Comparative Effectiveness of Noninvasive Ventilation vs Invasive Mechanical Ventilation in Chronic Obstructive Pulmonary Disease Patients With Acute Respiratory Failure.

J Hosp Med. 2013 Feb 11;

Authors: Tsai CL, Lee WY, Delclos GL, Hanania NA, Camargo CA

Abstract
BACKGROUND: Limited evidence exists on the comparative effectiveness of noninvasive ventilation (NIV) vs invasive mechanical ventilation (IMV) in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients with respiratory failure. OBJECTIVES: To characterize the use of NIV and IMV, and to compare the effectiveness of NIV vs IMV in AECOPD. DESIGN AND PATIENTS: Retrospective cohort study using data from the 2006-2008 Nationwide Emergency Department Sample. Emergency department visits for AECOPD with acute respiratory failure were identified with codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. MEASURES: The outcome measures were inpatient mortality, hospital length of stay, hospital charges, and complications. RESULTS: There were an estimated 101,000 visits annually for AECOPD with acute respiratory failure; 96% were admitted to the hospital. Of these, NIV use increased from 14% in 2006 to 16% in 2008 (P=0.049). Use of NIV, however, varied widely between hospitals, ranging from 0% to 100% with a median of 11%. Noninvasive ventilation was more often used in higher-case volume, Northeastern hospitals. In a propensity score analysis, NIV use, compared with IMV, was associated with lower inpatient mortality (risk ratio: 0.54, 95% confidence interval [CI]: 0.50-0.59), shortened hospital length of stay (-3.2 days; 95% CI: -3.4 to -2.9 days), lower hospital charges (-$35,012; 95% CI: -$36,848 to -$33,176), and lower risk of iatrogenic pneumothorax (0.05% vs 0.5%, P<0.001). CONCLUSIONS: Although NIV use is increasing in US hospitals, its adoption remains low and varies widely between hospitals. Our observational study suggests NIV appears to be more effective and safer than IMV for AECOPD in the real-world setting. Journal of Hospital Medicine 2013. © 2013 Society of Hospital Medicine.

PMID: 23401469 [PubMed - as supplied by publisher]