Perhaps airway smooth muscle dysfunction contributes to asthmatic bronchial hyperresponsiveness after all

Recently, a new phase cycling scheme was introduced by this laboratory for use in biological solid-state NMR experiments involving multiple pi-pulses with characteristics that suggested it may enhance the sensitivity of these kind of experiments (Y. Li and J. N. S. Evans, 1995, Chem. Phys. Lett. 241, 79 and Erratum, 1995, ibid. 246, 527; Y. Li and J. N. S. Evans, 1996, J. Magn. Reson. B 111, 296). The new sequence followed the supercycled concept proposed a decade ago for heteronuclear decoupling experiments. In this paper, more detailed experiments demonstrate that the claim of enhanced sensitivity was unfounded, and in fact the supercycle proposed differs little from the established XY-8 and XY-16 based supercycles.     

Muscarinic hyperresponsiveness of antigen-sensitized feline airway smooth muscle in vitro

OBJECTIVE: To determine the effect of in vivo antigen sensitization (Ascaris suum) of cats on tracheal smooth muscle (TSM) and bronchial smooth muscle (BSM) muscarinic reactivity in vitro. ANIMALS: Healthy domestic shorthair cats of either sex. PROCEDURE: Cats were sensitized and were long-term antigen (or sham) challenge exposed for 6 weeks by aerosolization with soluble Ascaris suum. Tracheal and BSM preparations were obtained and stimulated in vitro by electrical field stimulation (EFS), acetylcholine (ACh, a muscarinic agonist), and physostigmine (an AChase inhibitor). Responses were compared with responses of comparable tissues from sham antigen challenge-exposed cats. RESULTS: Tracheal and BSM from sensitized, compared with sham-sensitized (control), cats had greater isometric contraction (expressed as percentage of the response observed for isotonic, 63 mM KCl-elicited contraction [% KCl]) in response to endogenous (EFS) and exogenous muscarinic receptor activation (ACh). Contractions in response to EFS by TSM from control cats were 74% KCl vs 97% KCl for antigen-sensitized TSM (P < 0.04). Muscarinic responses were augmented comparably by in vivo sensitization; TSM from control cats contracted to 190% KCl vs 230% KCl (P < 0.03) for TSM from immune-sensitized cats. Physostigmine augmented responses of all tissues to ACh so that TSM from control (290% KCl) and antigen-sensitized (257% KCl) cats were similar. Responses of BSM from antigen-sensitized cats had similar augmentation of contractile response to EFS and ACh. CONCLUSIONS: Long-term in vivo antigen sensitization increases numbers of muscarinic receptors on airway smooth muscle or decreases the availability or activity of AChase in cats. CLINICAL RELEVANCE: Modulation of muscarinic receptors may be useful for treatment of asthmatic cats with in vivo airway hyperreactivity.     

Molecular mechanisms of the hyperresponsiveness of airway smooth muscle in bronchial asthma

Chronic neurobehavioral effects of acute sarin poisoning were evaluated in 9 male and 9 female patients who were exposed to sarin poisoning in the Tokyo subway incident in Japan. The investigators used nine neurobehavioral tests, as well as a posttraumatic stress disorder checklist, 6-8 mo after the poisoning occurred. Serum cholinesterase activity in patients on the day of poisoning (i.e., March 20, 1995) ranged from 13 to 131 IU/l (mean=72.1 IU/l). The results of analysis covariance, in which age, education level, alcohol consumption, and smoking status (covariates) were controlled in 18 sarin cases and in 18 controls, showed that the score on the digit symbol (psychomotor performance) test was significantly lower in the sarin cases than in controls. Nonetheless, the scores for the General Health Questionnaires, fatigue of Profile of Mood States, and posttraumatic stress disorder checklist were significantly higher in the sarin cases than controls. The investigators added posttraumatic stress disorder to the covariates, and only the score on the digit symbol test was significantly lower in sarin cases. In addition, the results of stepwise multiple regression analysis in 18 sarin cases revealed that scores for the General Health Questionnaires, fatigue of Profile of Mood States (i.e., fatigue, tension-anxiety, depression, and anger-hostility)-together with the paired-associate learning test-were associated significantly with posttraumatic stress disorder. The association did not remain significant for the digit symbol test score. Perhaps a chronic effect on psychomotor performance was caused directly by acute sarin poisoning; on the other hand, the effects on psychiatric symptoms (General Health Questionnaire) and fatigue (Profile of Mood States) appeared to result from posttraumatic stress disorder induced by exposure to sarin.     

Eosinophils are not required to induce airway hyperresponsiveness after nematode infection

Eosinophilic inflammation of the airways is believed to play a central role in the pathogenesis of bronchial asthma. Inoculation of mice with the nematode Nippostrongylus brasiliensis induces pulmonary inflammation, characterized by a marked infiltration of eosinophils, subsequent to the migration of parasites through the lungs. Infection is associated with polarized Th2 responses in different strains of mice tested. Thus, this model may be useful to determine the relationship between established pulmonary eosinophilic inflammation, Th2 immune responses and airway changes in a nonallergic background. In the present study, we have used IL-5-deficient mice to evaluate the role of IL-5 in eosinophilic lung inflammation and airway hyperresponsiveness (AHR). In wild-type C57B/6 mice, infection with N. brasiliensis resulted in eosinophil accumulation, associated with extensive lung damage characterized by hemorrhage and alveolar wall destruction, and a strong AHR following methacholine treatment. In IL-5-deficient mice, eosinophil infiltration and the associated lung damage was abrogated. Nonetheless, AHR was unimpaired. Our results suggest that eosinophil accumulation plays a central role in lung damage but is not responsible for the induction of airway constriction following N. brasiliensis infection.     

Effects of glucocorticoids and beta-adrenoceptor agonists on the proliferation of airway smooth muscle

An increase in airway smooth muscle is a characteristic feature of asthma. Because beta-adrenoceptor agonists and corticosteroids are commonly used in the treatment of asthma we have studied the effects of these medicines on the growth of airway smooth muscle. These agents were incubated with bovine airway smooth muscle cells for 40 h for measurement of thymidine incorporation and 64 h for measurement of cell counts. Salbutamol inhibited thymidine incorporation (IC50 = 60 nM) and led to a reduction in cell number (IC50 = 10 nM). At 10 microM there was a 14.6 +/- 2.6% reduction in cell number. Salmeterol also inhibited the growth of the airway smooth muscle cells but the effect did not plateau at 10 microM. At this concentration there was an 89.5 +/- 3.6% reduction in thymidine incorporation and a 44.1 +/- 5.2% reduction in cell number. Cortisol and beclomethasone dipropionate were more potent than salbutamol in inhibiting thymidine incorporation with IC50 values of 5 nM and 0.2 nM respectively. Cortisol 100 nM led to a 16.6 +/- 6.5% reduction and beclomethasone dipropionate 3 nM led to a 17.8 +/- 5.8% reduction in cell number. If similar effects occur in man and in vivo, these medicines could act directly on airway smooth muscle to inhibit the development of hyperplasia.     

CD4+ T cells can induce airway hyperresponsiveness to allergen challenge in the brown norway rat

Airway hyperresponsiveness to inhalational challenge with methacholine (MCh) develops by 32 h after allergen challenge of actively sensitized BN rats. To test the hypothesis that CD4+ T cells mediate allergen-induced hyperresponsiveness independent of IgE-mediated mechanisms, we administered CD4+ T cells, CD8+ T cells, and a mixture of CD4+ and CD8+ T cells (total T cells) isolated from the cervical lymph nodes of rats sensitized with ovalbumin (OA) to naive BN rats that underwent aerosol challenge with either OA or bovine serum albumin (BSA) 2 d later. Responsiveness to MCh was measured 2 d before transfer of T cells and 32 h after challenge with OA or BSA. Airway responsiveness increased significantly in recipients of CD4+ T cells after OA challenge, but not in any other of the treatment groups. Analysis of bronchoalveolar lavage (BAL) cells for major basic protein expression by immunostaining showed eosinophilia in OA-challenged CD4+ and total T-cell recipients. Cells retrieved by bronchoalveolar lavage showed increased expression of IL-5 mRNA (in situ hybridization) in CD4+ T cell recipients after OA challenge compared with other groups. Interferon-gamma mRNA was expressed to the greatest extent in CD8+ recipients, but it was elevated in both OA- and BSA-challenged animals. We conclude that CD4+ T cells can induce airway hyperresponsiveness after inhalational challenge with allergen and this is associated with IL-5 production and eosinophilia. CD8+ T cells may have a negative regulatory effect on responsiveness, possibly mediated by interferon-gamma.     

Ketamine relaxes airway smooth muscle contracted by endothelin

Endothelins (ETs) are synthesized not only in vascular endothelial cells but also in airway epithelial cells. Increased ET-1 has been demonstrated in bronchial epithelium of asthmatic patients, and, in severe asthma attacks, ET-1 increases in plasma and bronchoalveolar lavage fluid. In this study, we investigated whether ketamine (KET) relaxes ET-induced tracheal contractions. Female guinea pigs were killed with an overdose of pentobarbital. The trachea was removed and cut spirally into two strips that were mounted in an organ bath filled with Krebs-bicarbonate buffer. The response of each strip to 10(-7) M carbachol was taken as 100% contraction to which the response to ET was referred. The contribution of the epithelium to the relaxant effect of KET was studied in denuded tracheae or in the presence of 5 x 10(-5) M indomethacin. ET-1 (3 x 10(-8) M) induced contractions that were 76 +/- 3% of those induced by carbachol. KET reversed the response to ET-1 in a dose-dependent fashion. Similarly, ET-2 (3 x 10(-8) M) induced contractions that were 74 +/- 5% of those induced by carbachol, and KET also reversed this response in a dose-dependent manner. In epithelium-denuded strips, ET-1 induced contractions that were 104 +/- 3% of those induced by carbachol, and KET still reversed this response. The tonic phase of the response to ET-1 was equal (100 +/- 6%) to the response to carbachol, and KET did not affect it significantly. In the presence of ryanodine, KET reduced the ET-1-induced contraction from 67 +/- 2% to 36 +/- 3.%, P < 0.01. In the presence of nicardipine, KET also inhibited the ET-1-induced contraction. We conclude that KET relaxes the tracheal smooth muscle contracted by ETs via a mechanism that is independent of the tracheal epithelium. The relaxant effect of KET on the ET-induced contraction of the trachealis muscle is not dependent upon blockade of 1) sarcolemma influx of Ca2+ through the dihydropyridine Ca2+ channel or 2) the release of intracellular Ca2+ through the ryanodine-sensitive intracellular Ca2+ channel. It is likely that the action of KET relaxing ET-induced tracheal contractions is at some point of the inositol 1,4,5-trisphosphate signaling pathway.     

Isometric and isotonic contractions in airway smooth muscle

Canine tracheal smooth muscle was used as an in vitro model of smooth muscle in intrapulmonary airways to determine whether active tension curves derived from isometric and isotonic muscles are similar, and thus resemble striated muscle in this respect. Isometric, isotonic after-loaded, and isotonic free-loaded contractions elicited at different lengths and loads, were analysed. The data demonstrate that length-tension (L-T) diagrams were different in these various types of contractions for electrically and carbachol driven tracheal smooth muscles strips. In general, at any given length active tension is less in isotonic and free-loaded modes of contraction as compared with isometric. We conclude that the ability to actively develop tension at a given length in airway smooth muscle depends on the mode of contraction.     

Mitogen-activated signaling in cultured airway smooth muscle cells

Airway hyperresponsiveness and excess smooth muscle mass coexist in patients with asthma and bronchopulmonary dysplasia. This increase in airway smooth muscle mass, which in part relates to smooth muscle proliferation, may increase bronchoconstrictor-induced airway narrowing, even in the absence of excessive force generation. Thus, there is need for a precise understanding of the events involved in airway smooth muscle mitogenesis. This review examines the inflammatory substances and growth factors that induce airway smooth muscle proliferation, and the signaling pathways that may be involved in the transduction of these extracellular signals to the cell nucleus. Also discussed are various antimitogenic substances and potential mechanisms underlying the inhibition of cell proliferation. Central to the discussion are the extracellular signal regulated kinases (ERKs), serine/threonine kinases of the mitogen-activated protein kinase (MAP kinase) superfamily, which upon activation, translocate from the cytoplasm to the nucleus after mitogenic stimulation. Insight gained from studies of cultured airway smooth muscle growth and mitogen-activated signaling may shed light on parallel mechanisms that may operate in asthma and in bronchopulmonary dysplasia, and may lead to therapeutic interventions against airway remodeling.     

Mechanism of rhinovirus-induced changes in airway smooth muscle responsiveness

An important interplay exists between specific viral respiratory infections and altered airway responsiveness in the development and exacerbations of asthma. However, the mechanistic basis of this interplay remains to be identified. This study addressed the hypothesis that rhinovirus (RV), the most common viral respiratory pathogen associated with acute asthma attacks, directly affects airway smooth muscle (ASM) to produce proasthmatic changes in receptor-coupled ASM responsiveness. Isolated rabbit and human ASM tissue and cultured ASM cells were inoculated with human RV (serotype 16) or adenovirus, each for 6 or 24 h. In contrast to adenovirus, which had no effect, inoculation of ASM tissue with RV induced heightened ASM tissue constrictor responsiveness to acetylcholine and attenuated the dose-dependent relaxation of ASM to beta-adrenoceptor stimulation with isoproterenol. These RV-induced changes in ASM responsiveness were largely prevented by pretreating the tissues with pertussis toxin or with a monoclonal blocking antibody to intercellular adhesion molecule-1 (ICAM-1), the principal endogenous receptor for most RVs. In extended studies, we found that the RV-induced changes in ASM responsiveness were associated with diminished cAMP accumulation in response to dose-dependent administration of isoproterenol, and this effect was accompanied by autologously upregulated expression of the Gi protein subtype, Gialpha3, in the ASM. Finally, in separate experiments, we found that the RV-induced effects on ASM responsiveness were also accompanied by autologously induced upregulated mRNA and cell surface protein expression of ICAM-1. Taken together, these findings provide new evidence that RV directly induces proasthmatic phenotypic changes in ASM responsiveness, that this effect is triggered by binding of RV to its ICAM-1 receptor in ASM, and that this binding is associated with the induced endogenously upregulated expression of ICAM-1 and enhanced expression and activation of Gi protein in the RV-infected ASM.     

Ultrastructure, calcium accumulation, and contractile response in smooth muscle

After removing extracellular Ca2+ with [ethylene bis(oxyethylenenitrilo)]tetraacetic acid, we found that the guinea pig vas deferens (VD) was mechanically responsive to electrical stimulation for a significantly greater length of time than was guinea pig taenia coli (TC). An obvious explanation for these findings is that the VD has more intracellular calcium available for contraction than does the TC. To determine if this explanation is plausible, the volume of internal storage structures within the two muscles was compared. It was found that the volumes of potential sequestering structures in the VD and TC are not significantly different. Next, the affinities of the storage structures for calcium were compared. The VD was found to accumulate approximately twice as much 45Ca as did the TC, as determined by 45Ca autoradiography. Calcium-45 was present to a greater extent in association with surface vesicles, sarcoplasmic reticulum (SR), and mitochondria than in the unassociated state within the cytoplasmic matrix. Based on the results of these experiments, we suggest that the VD and the TC of the guinea pig differ in the affinity of their storage sites for calcium.     

Cervical smooth muscle contractile activity after treatment with mifepristone and progesterone

The biodistribution and pharmacokinetics of intra-arterially administered N-isopropyl-p[123I] iodoamphetamine (123I-IMP) were prospectively evaluated in 38 patients with histologically proven pulmonary or hepatic tumors. Intra-arterially infused 123I-IMP was distributed initially in peripheral tissues in which the blood supply was maintained. Its concentration in malignant neoplasms was demonstrated to be higher than in normal tissues. In pulmonary cancer, the tumor uptake of the administered dose without a tissue attenuation correction (% uptake) of 123I-IMP at 1-2 min after injection was 14.7 +/- 5.7% (s.d.). The tumor to normal tissue ratio was 2.1 +/- 0.7 in hepatocellular carcinoma and 1.4 +/- 0.7 in metastatic tumors. The biodistribution of 123I-IMP was also compared to that of 99mTc-macroaggregated albumin (99mTc-MAA) in 9 cases of hepatic cancer. The distribution of 123I-IMP resembled that of 99mTc-MAA in 5 cases and was different in 4 cases. 123I-IMP was more concentrated in the tumor than 99mTc-MAA. Intra-arterial infusion scintigraphy with 123I-IMP seems to provide information on effective blood supply to neoplasms which are targeted in interventional radiology.     

Cytoplasmic redox potential affects energetics and contractile reactivity of vascular smooth muscle

Variations in the cytoplasmic redox potential (Eh) and NADH/NAD ratio as determined by the ratio of reduced to oxidized intracellular metabolite redox couples may affect mitochondrial energetics and alter the excitability and contractile reactivity of vascular smooth muscle. To test these hypotheses, the cytoplasmic redox state was experimentally manipulated by incubating porcine carotid artery strips in various substrates. The redox potentials of the metabolite couples [lactate]/[pyruvate]i and [glycerol 3-phosphate]/[dihydroxyacetone phosphate]i varied linearly (r=0.945), indicating equilibrium between the two cytoplasmic redox systems and with cytoplasmic NADH/NAD. Incubation in physiological salt solution (PSS) containing 10 mm pyruvate ([lact]/[pyr]=0.6) increased O2 consumption approximately 45% and produced anaplerosis of the tricarboxylic acid (TCA cycle), whereas incubation with 10 mm lactate-PSS ([lact]/[pyr]i=47) was without effect. A hyperpolarizing dose of external KCl (10 mM) produced a decrease in resting tone of muscles incubated in either glucose-PSS (-0.8+/-0.8 g) or pyruvate-PSS (-2.1+/-0.8 g), but increased contraction in lactate-PSS (1.5+/-0.7 g) (n=12-18, P<0.05). The rate and magnitude of contraction with 80 mm KCl (depolarizing) was decreased in lactate-PSS (P=0.001). Slopes of KCl concentration-response curves indicated pyruvate>glucose>lactate (P<0.0001); EC50 in lactate (29. 1+/-1.0 mM) was less than that in either glucose (32.1+/-0.9 mm) or pyruvate (32.2+/-1.0 mM), P<0.03. The results are consistent with an effect of the cytoplasmic redox potential to influence the excitability of the smooth muscle and to affect mitochondrial energetics.     

Airway smooth muscle, tidal stretches, and dynamically determined contractile states

In the classic theory of airway lumen narrowing in asthma, active force in airway smooth muscle is presumed to be in static mechanical equilibrium with the external load against which the muscle has shortened. This theory is useful because it identifies the static equilibrium length toward which activated airway smooth muscle would tend if given enough time. The corresponding state toward which myosin-actin interactions would tend is called the latch state. But are the concepts of a static mechanical equilibrium and the latch state applicable in the setting of tidal loading, as occurs during breathing? To address this question, we have studied isolated, maximally contracted bovine tracheal smooth muscle subjected to tidal stretches imposed at 0.33 Hz. We measured the active force (F) and stiffness (E), which reflect numbers of actin-myosin interactions, and hysteresivity (eta) which reflects the rate of turnover of those interactions. When the amplitude of imposed tidal stretch (epsilon) was very small, 0.25% of muscle optimal length, the steady-state value of F approximated the isometric force, E was large, and eta was small. When epsilon was increased beyond 1%, however, F and E promptly decreased and eta promptly increased. The muscle could be maintained in these steady, dynamically determined contractile states for as long as the tidal stretches were sustained; when epsilon subsequently decreased back to 0.25%, F, E, and eta returned slowly toward their previous values. The provocative stretch amplitude required to cause active force or muscle stiffness to fall by half, or hysteresivity to double, was slightly greater than 2%. These observations are consistent with a direct effect of stretch upon bridge dynamics in which, with increasing tidal stretch amplitude, the number of actin-myosin interactions decreases and their rate of turnover increases. We conclude that the interactions of myosin with actin are at every instant tending toward those that would prevail in the isometric steady state, but tidal changes of muscle length cause an excess in the rate of detachment. These stretch-induced detachment events can come so fast compared with the rate of attachment that static equilibrium conditions are never attained. If so, then airway lumenal narrowing and the underlying contractile state would be governed by a dynamic mechanical process rather than by a mechanical equilibrium of static forces.     

Arachidonic acid-induced calcium signalling in human airway smooth muscle cells

Until now computer-assisted parasite identification was based on database applications requiring data specification on an individual basis, thus limiting the ability of the system to handle rule-based knowledge as humans are used to do. A new Expert PArasite IdentificatiON (EPAION: Greek term for expert) system was developed to serve as an interface between the database and the user, where the database is a repository for bionomic and morphological facts about the parasites for the expert system. The system was developed by using a logic-based computer language which allows the definition of rules and facts to assist the creation of queries to the database. The components of the system are the knowledge base, the multimedia data base, the inference mechanism, and the graphical user interface. The operational modules of the system are the Parasite Identifier and the system Utilities. This expert system facilitates knowledge incorporation in a manner simulating the natural mental process, thus allowing the checking of the accuracy of the information that the user feeds to the computer and the creation of intelligent queries to the database. These characteristics accelerate focusing and optimize the parasite identification scheme regardless of the user's profile of competency.     

Time-course of antigen-induced airway inflammation in the guinea-pig and its relationship to airway hyperresponsiveness

The causative relationship between airway inflammation and hyperreactivity is unclear, since inflammatory changes have been examined at one or, at most, a few time-points after antigen challenge in both human asthma and animal models. We have made a detailed investigation of inflammatory and functional changes in the airways up to 8 days after antigen challenge in guinea-pigs. In particular, we examined the hypothesis that eosinophil-derived mediators contribute to tissue damage and the development of airway hyperresponsiveness. Following antigen challenge, the influx of inflammatory cells and mediator release in airway tissue and bronchoalveolar lavage fluid were correlated temporally with histopathological changes in airway tissue and airway responsiveness. Eosinophil influx was demonstrable at 4 h. Eosinophilia peaked after 24 h and persisted for at least 8 days. Parallel increases in the concentrations of major basic protein and eosinophil cationic protein in bronchoalveolar lavage fluid indicated that the eosinophils were activated. Eosinophilia was accompanied by subepithelial oedema and epithelial damage co-localized with major basic protein immunoreactivity. A transient neutrophilia (< 48 h duration) and an increase in neutrophil elastase in bronchoalveolar lavage fluid peaked at 14 h. The proportion of airway macrophages with an activated morphology increased at 8 h and remained markedly elevated until 72 h. Airways were hyperresponsive to histamine at 4 h and for at least 8 days. The antigen-induced airway inflammation resemble in time-course and histopathology that seen in antigen-challenged asthmatics, and indicate that the eosinophil and its cytotoxic proteins may be major mediators of airway mucosal damage and airway hyperresponsiveness.     

Expression of cyclo-oxygenase-2 in human airway smooth muscle is associated with profound reductions in cell growth

1. It is now accepted that uncontrolled proliferation of human airway smooth muscle (HASM) cells contributes, in many cases, to the chronic stages of asthma. However, the physiological and pathophysiological processes regulating cell growth and division in the airway are not clear. We have recently shown that the immediate early gene, cyclo-oxygenase-2, is induced by cytokines in HASM cells. Since cyclo-oxygenase metabolites, such as prostaglandin (PG) E2 have been shown to modulate HASM cell growth, we have investigated any autocrine action of endogenously released cyclo-oxygenase-1/2 products on the proliferative responses in these cells. 2. HASM cells were cultured from healthy tissue obtained at lung or heart/lung transplantation. HASM cell proliferation was measured by [3H]-methyl thymidine uptake by cells and by cell counts. Cyclo-oxygenase-2 expression was measured by Western blot analysis and activity measured by the release of PGE2, by radioimmunoasay. 3. HASM cells proliferated in response to foetal calf serum, a response that was greatly inhibited when cyclo-oxygenase-2 was induced with either interleukin-1beta plus tumour necrosis factor-alpha or interleukin-1beta, tumour necrosis factor alpha plus interferon gamma (each at 10 ng ml(-1)). The inhibitory effect of cytokines on HASM cell proliferation was reversed in a concentration dependent manner by either the mixed cyclo-oxygenase-1/-2 inhibitor, indomethacin or the selective cyclo-oxygenase-2 inhibitor, L-745,337 (each at 10 microM). 4. PGE2 or the stable analogue of prostacyclin, cicaprost concentration-dependently (0.1 pmol to 1 microM) inhibited serum induced proliferation of HASM cells. By contrast, the TP receptor agonist, U46619 stimulated proliferation of HASM cells when cells were cultured without but not with serum. Other cyclo-oxygenase products, PGD2, PGF2alpha had no effect on cellular proliferation at concentrations up to 1 microM. 5. These observations illustrate a profound inhibitory effect of cyclo-oxygenase-2 induction on HASM cell proliferation, possibly via IP or EP receptor activation. Cyclo-oxygenase-2 induction has, thus far, been associated with the pro-inflammatory responses of plasma exudation and oedema formation and is assumed to be an enzyme worthy of selective inhibition in many disease states. However, our observations suggest that cyclo-oxygenase-2 can have an anti-inflammatory, anti-proliferative function in the airways. These observations may have importance in the use and development of therapies for airway disease such as asthma.     

Effect of stretch on the contractile response of isolated portal vein smooth muscle

The character of spontaneous activity of the isolated preparation was shown to be affected only by the first stretching stimulus which was due to release of the intracellular Ca. Active contractile responses to stretching at the peak of the contracture due to perfusion of the preparations with the Krebs sodiumless solution, are directly correlated with the speed of the stretching. Stretching of the preparations in calciumless solution elicited no active response.