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There is a pressing requirement to develop new therapies for chronic obstructive pulmonary disease (COPD), as current therapies fail to prevent disease progression or mortality and do not deal with the underlying inflammatory process. The mainstay of current drug therapy is long-acting bronchodilators, but no treatments suppress chronic inflammation in COPD, which is corticosteroid-resistant. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several novel therapeutic targets have been identified, leading to the development of various mediator antagonists, novel broad-spectrum anti-inflammatory treatments and drugs that may reverse the molecular mechanisms of corticosteroid resistance.
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The effects of inhaled platelet activating factor were compared with those of inhaled methacholine (control) on airway calibre, airway responsiveness to methacholine and isoprenaline, and circulating cells in eight subjects with mild, stable asthma. Platelet activating factor was given in six doses at 15 minute intervals and airway response measured as change in partial expiratory flow at 30% of vital capacity (Vp30). Platelet activating factor caused a fall in Vp30, the mean (SEM) maximum percentage fall being 28.9 (4.2) five minutes after the first dose (12 micrograms) and 50.9 (8.0) after the second dose (24 micrograms). Tachyphylaxis occurred, however, with the four subsequent doses of inhaled platelet activating factor. There was transient neutropenia after the first dose, from a mean of 3.6 (0.2) x 10(9) to 2.2 (0.5) x 10(9) neutrophils/l; this response also showed tachyphylaxis with subsequent doses. The mean PC40 (the concentration of methacholine needed to cause a 40% fall in Vp30) was unchanged one, three, and seven days after administration of platelet activating factor. There was no significant correlation between baseline PC40 methacholine and the maximal fall in Vp30 after either the first (12 micrograms) or the second dose (24 micrograms) of platelet activating factor. The control challenge with methacholine produced a degree of bronchoconstriction similar to that of platelet activating factor but was not associated with any significant change in bronchial responsiveness or in circulating cells. The bronchodilator response to inhaled isoprenaline measured three days after inhalation of platelet activating factor and of methacholine was similar after the two challenges. Thus asthmatic subjects who are hyperresponsive to methacholine show a similar bronchoconstrictor response to platelet activating factor, as has been observed in normal subjects; overall this did not cause airway hyperresponsiveness to methacholine.
Furosemide, a loop diuretic, is known to inhibit the response to a variety of indirect bronchial challenges in humans but does not inhibit bronchoconstriction induced by inhaled methacholine or histamine. We have investigated the effects of the two loop diuretics, furosemide (10−6 to 10−3 M) and bumetanide (10−7 to 10−4 M), on airway smooth muscle contraction in vitro induced by electrical field stimulation (EFS), or exogenously applied acetylcholine (ACh) or substance P (SP) in guinea pig tracheal and bronchial smooth muscle strips pretreated with indomethacin (10−5 M) and propranolol (10−6 M). Both furosemide and bumetanide caused a concentration-dependent inhibition of cholinergically mediated neural contraction in the trachea. The effect of furosemide was not influenced by the presence of airway epithelium. Furthermore, both furosemide and bumetanide inhibited in a concentration-dependent fashion nonadrenergic, noncholinergic (NANC) contraction induced by electrical field stimulation of bronchi pretreated with atropine (10−6 M). Neither drug at the highest concentration inhibited the responses to exogenous acetylcholine (10−8 to 10−2 M) or substance P (10−9 to 10−5 M). Thus loop diuretics inhibit the neurally induced contraction of guinea pig airways without a direct effect on airway smooth muscle. We conclude that loop diuretics inhibit both cholinergic and excitatory NANC neurotransmission in guinea pig airways and that this effect may be related to their inhibitory effects on the sodium-potassium-chloride cotransporter.
Sarcoidosis is a granulomatous inflammatory disease that is induced by unknown antigen(s) in a genetically susceptible host. Although the direct link between Mycobacterium tuberculosis (MTB) infection and sarcoidosis can be excluded on the basis of current knowledge, non-infectious mechanisms may explain the causative role of mycobacterial antigens. Ever since sarcoidosis was first described, its relationship with tuberculosis (TB) has been under-investigated. Whereas some researchers consider sarcoidosis and TB as two examples of the same disease process, others have rejected mycobacteria as playing any causative role in sarcoidosis. Whether they are linked causally or not, clinical evidence makes a differential diagnosis between the two conditions very challenging, particularly in countries with high burden of TB. The present study analyzes the relationship between sarcoidosis and TB and its implications in clinical practice. The coincidence of TB and sarcoidosis and the higher incidence of mycobacterial DNA in biological samples of sarcoid patients have been reported by many authors. In addition, new evidence of a similarity in MTB phenotype in sarcoidosis is provided. Overall, these observations suggest that TB and sarcoidosis may not only share the same etiology, but may even be different aspects of one disease.
The effect of 5‐hydroxytryptamine (5‐HT) was studied on excitatory neurally mediated non‐adrenergic non‐cholinergic (NANC) contractions evoked by electrical field stimulation (EFS) in guinea‐pig isolated bronchi. 5‐HT (0.1–100 μ m ) produced a concentration‐dependent inhibition of the excitatory NANC response with 50.9 ± 5.0% ( n = 5, P < 0.01) inhibition at 100 μ m . This inhibition was not significantly affected by the 5‐HT 2 antagonist, ketanserin (1 μ m ) when inhibitions (± ketanserin) at each concentration of 5‐HT were compared by unpaired t tests; however, this concentration appeared to produce a leftward shift (∼ 10 fold) of the 5‐HT concentration‐inhibition curve. Ketanserin (1 μ m ) was effective in blocking bronchoconstriction evoked by activation of 5‐HT 2A receptors on airway smooth muscle. In the presence of ketanserin (1 μ m ) 5‐HT (100 μ m ) evoked an inhibition of 57.4 ± 5.9% ( n = 5, P < 0.01) with an EC 50 of 0.57 μ m . Inhibition evoked by 5‐HT (0.1–100 μ m ) was unaffected by the α‐adrenoceptor antagonist phentolamine (1 μ m ), the β 2 ‐adrenoceptor antagonist, ICI 118551 (0.1 μ m ), the 5‐HT 1A/B antagonist, cyanopindolol (1 μ m ) or the 5‐HT 3/4 antagonist, ICS 205–930 (1 μ m ). Methiothepin (0.1 μ m ) produced an insurmountable inhibition of the effect of 5‐HT (0.1–100 μ m ), reducing the maximum inhibition produced by 5‐HT (100 μ m ) to 30.2 ± 5.0% ( n = 5, P < 0.001) and suggesting a non‐competitive antagonism. Methiothepin inhibited the effect of 5‐HT (10 μ m ) in a concentration‐dependent manner with an IC 50 of 81 n m . Selective 5‐HT receptor agonists were also tested on excitatory NANC responses. 5‐Carboxamidotryptamine (5‐CT, 0.1–100 μ m ) was the most potent, producing a concentration‐dependent inhibition with an EC 50 of 0.13 μ m . Calculation of approximate IC 25 values (concentration of the agonist required to give a 25% inhibition of the excitatory NANC response) gave a rank order of potency 5‐CT ≥ 5‐HT ≫ 8‐hydroxy‐dipropylaminotetralin (8‐OH‐DPAT) > α‐methyl‐5‐hydroxytryptamine (α‐Me‐5HT). Sumatriptan, 5‐methoxytryptamine (5‐MeOT) and 2‐methyl‐5‐hydroxytryptamine (2‐Me‐5HT) were essentially inactive with IC 25 > 100 μ m . 5‐HT (10 μ m ) did not significantly affect contractile responses to exogenously applied substance P (1 n m − 10 μ m ). The effect of 5‐HT was unchanged after incubation with the nitric oxide (NO) synthase inhibitor l ‐N G ‐nitroarginine methyl ester ( l ‐NAME, 100 μ m ). However, pretreatment with charybdotoxin (ChTX, 0.1–30 n m ), a blocker of the large conductance Ca 2+ ‐activated K + channel (K + Ca ), produced a concentration‐dependent inhibition of the effect of 5‐HT (10 μ m ). 5‐HT evokes a concentration‐dependent inhibition of e‐NANC bronchoconstriction in guinea‐pig isolated bronchi but does not affect cumulative concentration‐dependent contractile responses to substance P, suggesting that inhibition is via a prejunctional receptor. Effects of selective antagonists and agonists suggest that an atypical 5‐HT receptor mediates this inhibition. The inhibitory effect of 5‐HT does not involve the production of NO, but may involve the opening a ChTX‐sensitive K + Ca channel. These data suggest that an atypical 5‐HT receptor inhibits the release of neuropeptides from sensory C fibres and may act as other inhibitory neuromodulators via the opening of a common K + channel.
conferred without the need for coronary stent placement.'
The current coronary bioresorbable scaffolds (BRSs) are composed of either an aliphatic polymer or bioresorbable metal alloy. Numerous different polymers are available, each with different chemical compositions, mechanical properties, and subsequent bioresorption times. The purpose of this chapter is to facilitate the understanding of mechanical features of the materials used for bioresorbable scaffolds.
