Matrix Metalloproteinases in the Pathogenesis of Asthma and COPD

While asthma is an inflammatory disorder of the airways involving mediators released from mast cells and eosinophils, inflammation alone is insufficient to explain the chronic nature of the disease. Recent progress in the understanding of disease pathogenesis has revealed that airway remodeling, which is at least in part due to an excess of extracellular matrix (ECM) deposition in the airway wall, plays a significant role in airflow obstruction. Matrix metalloproteinases (MMPs) have been suggested to be the major proteolytic enzymes to induce airway remodeling in asthma and COPD. It has been widely accepted that different inflammatory processes are involved in asthma and COPD with different inflammatory cells, mediators, and responses to treatments. Despite these different processes, airflow obstruction and airway remodeling characterize these two diseases. MMP-2 and -9 have been reported to be involved in the pathogenesis of airway remodeling in both diseases and MMP-12, in addition to these MMPs, in the pathogenesis of COPD. In this review, we discuss the current views on the role of MMPs in the pathogenesis of bronchial asthma and COPD. Anti-MMP therapy could theoretically be useful to prevent airway remodeling in asthma and COPD. However, to date no clinical data are available regarding the efficacy of anti-MMP therapies in the treatment of patients with asthma and COPD.     

Falling asleep while driving and automobile accidents among patients with obstructive sleep apnea-hypopnea syndrome

Among 448 patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), 40 patients (8.9%) had been involved in one or more automobile accidents during the preceding 5 years. The main cause of these accidents was falling asleep while driving. Excessive sleepiness during driving was associated with an Epworth sleepiness scale (ESS) score of > 11 and/or an apnea-hypopnea index (AHI) of > 15. The automobile accident rate among 182 patients with severe OSAHS (AHI > 30) was significantly higher than the rate among 106 simple snorers (AHI < 5). Although four of the simple snorers were involved in automobile accidents, their ESS scores were all very high (15 or more).     

NEUTRAL ENDOPEPTIDASE 3.4.24.11 INHIBITION POTENTIATES THE INHIBITORY EFFECTS OF TYPE-C NATRIURETIC PEPTIDE ON LEUKOTRIENE D4-INDUCED AIRWAY CHANGES

1. Microvascular leakage, a primary feature of inflammation, is well known for worsening the asthmatic condition. Gene expression of and a specific receptor for type-C natriuretic peptide (CNP), initially considered a neuropeptide, have been detected in the human vascular wall and secretion of CNP from vascular endothelial cells has recently been demonstrated. These facts suggest the presence of a vascular natriuretic peptide system and led us to expect that CNP may act beneficially on airway microvascular leakage in asthma. In the present study, we investigated the effects of CNP against leukotriene (LT) D4 -induced airway microvascular leakage and bronchocon-striction and how these effects were potentiated by thiorphan, a potent neutral endopeptidase 3.4.24.11 (NEP) inhibitor. 2. Anaesthetized male guinea-pigs, ventilated via a tracheal cannula, were placed into a plethysmograph for 10 min, in order to measure pulmonary mechanics and mean blood pressure, after challenge with 2 μg/kg LTD₄ and then the extravasation of 20 mg/kg Evans blue dye into airway tissue was investigated to indicate and evaluate microvascular leakage. 3. Intravenous administration of CNP (100, 300 and 1000 μg/kg) significantly inhibited the LTD₄-induced microvascular leakage and bronchoconstriction in a dose-dependent manner. These inhibitory effects were enhanced by pretreatment with 20 mg/kg thiorphan, suggesting the important role of NEP in the pulmonary metabolism of CNP. 4. We believe that these results are encouraging for the further investigation of the therapeutic applications of exogenous CNP in asthma.     

Relaxant effects of forskolin on guinea pig tracheal smooth muscle

We investigated the relaxant effects of forskolin, a diterpene derivative isolated from the roots ofColeus forskohlii, on guinea pig airway smooth muscle by measuring the isometric tension of tracheal smooth muscle in vitro and transcutaneous Po₂ during the histamine inhalation test (HIT) in vivo. Forskolin (10⁻⁹–10⁻⁵ M) caused dose-dependent relaxant effects on resting tone and on leukotriene C₄ (10⁻⁷ M)-, leukotriene D₄ (10⁻⁷ M)-, and carbachol (3 × 10⁻⁶ M)-induced contraction of tracheal smooth muscle. Moreover, with propranolol pretreatment the relaxant effect of forskolin on tracheal smooth muscle did not change, whereas with the same pretreatment the relaxant effect of isoproterenol diminished. Forskolin (10⁻⁸–10⁻⁶ M) raised tissue cyclic AMP levels dose-dependently in tracheal smooth muscle (6.7–359.9 pmol/mg protein). Forskolin (1 mg/kg) administered subcutaneously raised the respiratory threshold of (RT-histamine in the HIT. The determination of the RT-histamine by measuring tcPo₂ was possible without anesthesia. These results suggest that forskolin relaxes airway smooth muscle in guinea pigs in vitro and in vivo by raising tissue cyclic AMP levels and that its actions are independent ofβ-adrenoceptors.     

Prognostic factors in rapidly progressive interstitial pneumonia

Background and objective: The aim of the present study was to examine clinical and other features that might allow prognostic distinctions between histological patterns in presentations with rapidly progressive interstitial pneumonia (RPIP), and to assess prognostic factors for survival. Methods: Patients with RPIP among 425 consecutive patients with diffuse lung disease, who underwent surgical lung biopsy, were studied retrospectively. The discriminatory value of clinical and investigative features for identifying disease with a better outcome was evaluated. An a priori comparison was made between diffuse alveolar damage (DAD)/usual interstitial pneumonia with DAD pattern (Group A), and organizing pneumonia/non‐specific interstitial pneumonia pattern (Group B). Results: Twenty‐eight patients (6.6%) fulfilled the criteria for RPIP. The diagnosis was Group A disease in 15 (DAD in 10, usual interstitial pneumonia with DAD in 5), and Group B disease in 13 (organizing pneumonia in 8, non‐specific interstitial pneumonia in 5). There were no significant differences in initial findings between the groups. Prognosis was significantly better for Group B patients than for Group A patients (P = 0.021). Neither BAL nor parenchymal high‐resolution CT score was indicative of therapeutic responsiveness or outcome. Distinction between Group A and Group B on the basis of disease pattern was the only significant determinant of prognosis. Conclusions: RPIP included varied histological patterns with different outcomes, and in many cases these could not be predicted using baseline clinical data. Histology was the only significant predictor of ultimate prognosis.     

Changes in muscarinic acetylcholine receptors in guinea-pig lung: Effects of aging,inhalation of an allergen,administration of drugs,and vagotomy

This study was undertaken to investigate the effects of aging; inhalation of Konjak-Maiko, a typical Japanese allergen; administration of various drugs; and unilateral cervical vagotomy on muscarinic acetylcholine receptors (MAchR) in guinea-pig lung. We assessed the characteristics of MAchR by determining the affinity and the density of MAchR using [³H]quinuclidinyl benzilate, a potent muscarinic antagonist. A significant decrease in the density of MAchR was observed at 6 months of age and this decrease became more prominent until 2 years of age. No significant change in the affinity of MAchR was noted through the experimental period. Inhalation of Konjak-Maiko (60 min/day, for 10 days) did not affect either the affinity or the density of the receptors. Administration of ipratropium bromide (0.1 mg/kg/day, for 10 days) or prednisolone acetate (2 mg/kg/day, for 7 days) did not affect the characteristics of the receptors. In contrast to these drugs, diisopropyl fluorophosphate, an irreversible acetylcholinesterase inhibitor, produced a 26% reduction in the density without affecting the affinity of the receptors. The right cervical vagotomy increased the density of MAchR in the right lung by 17% without affecting the affinity of MAchR. These results suggest that the density of MAchR in lung may be controlled by changes in the activity of the receptors.     

Sleep-disordered breathing in patients with idiopathic cardiomyopathy.

BACKGROUND: Sleep-disordered breathing may adversely affect heart function, and thereby contribute to the progression of heart failure. A study was undertaken in patients with idiopathic cardiomyopathy to document the characteristics of sleep-disordered breathing. METHODS AND RESULTS: Thirty-five patients with a diagnosis of idiopathic cardiomyopathy, comprising 20 patients with dilated cardiomyopathy (DCM) and 15 patients with hypertrophic cardiomyopathy (HCM), underwent overnight polysomnography. Of these 35, 16 (80%) of the DCM patients and 7 (47%) of the HCM patients had sleep-disordered breathing. Central sleep apnea-hypopnea syndrome (CSAHS) was seen in 10 DCM patients, but not in the HCM patients, and obstructive sleep apnea-hypopnea syndrome (OSAHS) was seen in 6 DCM patients and 7 HCM patients. CSAHS was seen in DCM patients with a low left ventricular ejection fraction. HCM patients with OSAHS had a significantly greater body mass index (BMI) than those without OSAHS and CSAHS (27.6 +/- 3.8 vs 22.0 +/- 4.0 kg/m2, p<0.05). DCM patients with OSAHS had a larger BMI than those with CSAHS (29.3 +/- 5.8 vs 24.2 +/- 4.0 kg/m2, p<0.05) and those without OSAHS and CSAHS (29.3 +/- 5.8 vs 21.3 +/- 3.1 kg/m2, p<0.05). CONCLUSIONS: Sleep-disordered breathing is common in patients with idiopathic cardiomyopathy; half of DCM patients had CSAHS, which was closely associated with obesity.     

Automatic segmentation and recognition of anatomical lung structures from high-resolution chest CT images.

This paper describes a fully automated segmentation and recognition scheme, which is designed to recognize lung anatomical structures in the human chest by segmenting the different chest internal organ and tissue regions sequentially from high-resolution chest CT images. A sequential region-splitting process is used to segment lungs, airway of bronchus, lung lobes and fissures based on the anatomical structures and statistical intensity distributions in CT images. The performance of our scheme is evaluated by segmenting lung structures from high-resolution multi-slice chest CT images from 44 patients; the validity of our method was proved by preliminary experimental results.