Cytokines play a critical role in orchestrating and perpetuating inflammation in asthmatic airways and several specific cytokine and chemokine inhibitors are now in development for the treatment of asthma. Inhibition of IL-4 with soluble IL-4 receptors has shown promising early results in asthma. Anti-IL-5 antibody is very effective at inhibiting peripheral blood and airway eosinophils but does not appear to be effective in symptomatic asthma. Inhibitory cytokines, such as IL-10, interferons, and IL-12 are less promising because systemic delivery produces intolerable side effects. Inhibition of TNF-α may be useful in severe asthma. Many chemokines are involved in the inflammatory response of asthma, and small-molecule inhibitors of chemokine receptors are in development. CCR3 antagonists are now in clinical development for the treatment of asthma. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful. Several such classes of drug are now in clinical development, and the risk of side effects with these nonspecific inhibitors may be reduced by the inhaled route of delivery.
1. Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kg-1 i.v.). The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7-44.6 nmol). 2. The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD100 = 3.0, 95% c.i. 0.98-8.9, and 2.0 nmol, 95% c.i. 0.65-6.2 nmol, respectively). 3. The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40-11.7) and 1.8 nmol (95% c.i. 0.87-3.5 nmol), respectively. 4. After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose-response curve for the effect of instilled BK (PD100 = 1.1 nmol, 95% c.i. 0.37-3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5. The kinase I inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD100 = 14.6 nmol, 95% c.i. 6.7-32.0 nmol). 6. These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved.
Intracoronary stents may be effective when used as "bail-out" devices for acute complications after percutaneous transluminal coronary angioplasty. Furthermore, preliminary reports have demonstrated some promising results with stents with regard to the reduction of restenosis. Several stent devices are available for preclinical and clinical evaluation. The use of these stainless-steel stents has been limited by poor visibility during fluoroscopy and thrombogenicity during the first days to weeks after implantation. We therefore investigated the immediate and short-term effects on arterial patency of a new, radiopaque, balloon-expandable coil stent in normal coronary arteries of pigs.In 10 animals, a stent was placed in two of the three epicardial coronary arteries. During the implantation procedure, the animals received heparin; after the procedure, no antithrombotic drugs were administered. After 1 week (five animals and 10 stents) or 4 weeks (five animals and 10 stents), repeat angiography was performed, followed by pressure-fixation of the coronary arteries for light and electron microscopic examination. Angiographic analysis revealed that all stented coronary segments were patent and without signs of intraluminal defects. Scanning electron microscopy showed complete endothelial covering of all stents within 7 days. Light microscopy showed a reduced tunica media locally under the stent wires, which resulted from exerted pressure. The neointima on top of the stent wires measured 56 microns (range, 42-88 microns) after 1 week and 139 microns (range, 84-250 microns) after 4 weeks.Results from this study show that this radiopaque endoprosthesis can be safely placed in normal coronary arteries of pigs. After 4 weeks, all stents were patent and there was no need for additional antithrombotic treatment, whereas neointimal proliferation was limited.
No abstract is provided for this article.
No abstract is provided for this article.
Chronic obstructive pulmonary disease (COPD) is regarded as a disease of accelerated lung aging. This affliction shows all of the hallmarks of aging, including telomere shortening, cellular senescence, activation of PI3 kinase-mTOR signaling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence, and a low-grade chronic inflammation (inflammaging). Many of these pathways are driven by chronic exogenous and endogenous oxidative stress. There is also a reduction in antiaging molecules, such as sirtuins and Klotho, which further accelerate the aging process. COPD is associated with several comorbidities (multimorbidity), such as cardiovascular and metabolic diseases, that share the same pathways of accelerated aging. Understanding these mechanisms has helped identify several novel therapeutic targets, and several drugs and dietary interventions are now in development to treat multimorbidity.
Journal Article Why Ca2$ antagonists will be most useful before or during early myocardial ischaemia and not after infarction has been established Get access P. G. HUGENHOLTZ, P. G. HUGENHOLTZ Thoraxcenter, Erasmus University Hospital RotterdamThe Netherlandsthe Physiologic Institute, Albert Ludwigs UniversitFreiburg, F.R.G. and University of MelbourneHeidelberg, Australia Correspondence should be addressed to Prof. P. G. Hugenholtz Search for other works by this author on: Oxford Academic PubMed Google Scholar P. W. SERRUYS, P. W. SERRUYS Thoraxcenter, Erasmus University Hospital RotterdamThe Netherlandsthe Physiologic Institute, Albert Ludwigs UniversitFreiburg, F.R.G. and University of MelbourneHeidelberg, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar A. FLECKENSTEIN, A. FLECKENSTEIN Thoraxcenter, Erasmus University Hospital RotterdamThe Netherlandsthe Physiologic Institute, Albert Ludwigs UniversitFreiburg, F.R.G. and University of MelbourneHeidelberg, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar W. NAYLER W. NAYLER Thoraxcenter, Erasmus University Hospital RotterdamThe Netherlandsthe Physiologic Institute, Albert Ludwigs UniversitFreiburg, F.R.G. and University of MelbourneHeidelberg, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar European Heart Journal, Volume 7, Issue 4, April 1986, Pages 270–278, https://doi.org/10.1093/oxfordjournals.eurheartj.a062064 Published: 01 April 1986 Article history Received: 10 July 1985 Revision received: 07 October 1985 Published: 01 April 1986
The measurement of exhaled NO has excited considerable interest, as it may provide a simple noninvasive means of measuring airways inflammation. There is now persuasive evidence that levels of NO are increased in association with airway inflammation and are decreased with anti-inflammatory treatment. Correlation of exhaled NO with more direct measurements of inflammation in the airways, such as induced sputum, bronchoalveolar lavage and bronchial biopsies, is needed. The great advantage of exhaled NO is that the measurement is completely noninvasive. It can, therefore, be performed repeatedly, and also in children and patients with severe airflow obstruction, where more invasive techniques are not possible. However, the measurement is not specific, and exhaled NO is increased in inflammation due to asthma, bronchiectasis, and respiratory tract infections. This means that absolute values are less important than serial measurements in individual patients. The value of this approach has been demonstrated in asthmatic patients, where the dose of inhaled steroid is changed, resulting in increased levels when the dose is reduced and lower levels when the dose is increased. Because exhaled NO is reduced by anti-inflammatory treatments, it may be of use in monitoring whether therapy is adequate. The technique may also have application in the monitoring of the anti-inflammatory effects of new antiasthma drugs, such as selective phosphodiesterase inhibitors, leukotriene antagonists and synthesis inhibitors, and immunomodulators. Because the measurement is precise and reasonably reproducible, it may facilitate the measurement of dose-response effects with anti-inflammatory treatments, which is difficult at present. The analysers for exhaled NO that are currently available are expensive, but in the future it is likely that technological advances will make it possible to miniaturize these analysers, so that they are portable and may even be used at home in conjunction with peak flow meters. -his may lead to their application in epidemiological research, which may be a useful screening measurement for community studies. Although we have discussed exhaled nitric oxide, other volatile substances may also be detected in exhaled air. Thus, ethane and pentane, which are volatile products of lipid peroxidation, and hydrogen peroxide, may be used to detect oxidant stress in the respiratory tract and may also be useful as markers of inflammation. There is little doubt that this is a rapidly expanding area of research.
PAF has many inflammatory effects in the airways and closely mimics the pathophysiology of asthma. PAF is a potent stimulus to eosinophil accumulation and activation and may be involved in the eosinophilic inflammation which characterises asthma and airway hyperresponsiveness.
