Treating asthma means treating airway smooth muscle cells.

Asthma is characterised by airway hyperresponsiveness, airway inflammation and airway remodelling. Airway smooth muscle cells are known to be the main effector cells of airway narrowing. In the present paper, studies will be discussed that have led to a novel view of the role of airway smooth muscle in the pathogenesis of asthma in which airway hyperresponsiveness, remodelling and inflammation are, at least in part, attributable to airway smooth muscle. Furthermore, how this new view may lead to a change in the phenotyping and treatment of patients with asthma will be discussed.

Sensitized airway smooth muscle plasticity and hyperreactivity: a review.

To help elucidate the mechanisms underlying asthmatic bronchospasm, the goal of our research has been to determine whether airway smooth muscle (ASM) hyperreactivity was the responsible factor. We reported that in a canine model of asthma, the shortening capacity (DeltaLmax) and velocity (Vo) of in vitro sensitized muscle were significantly increased. This increase was of sufficient magnitude to account for 75% narrowing of the in vivo airway, but maximal isometric force was unchanged. This last feature has been reported by others. Under lightly loaded conditions, ASM completes 75% of its isotonic shortening within the first 2 s. Furthermore, 90% of the increased shortening of ragweed pollen-sensitized ASM (SASM), compared with control (CASM), is complete within the first 2 s. The study of shortening beyond this period will apparently not yield much useful information, and studies of isotonic shortening should be focused on this interval. Although both CASM and SASM showed plasticity and adaptation with respect to isometric force, neither muscle type showed a difference in the force developed in these phases. During isotonic shortening, no evidence of plasticity was seen, but the equilibrated SASM showed increased DeltaLmax and Vo of shortening. Molecular mechanisms of changes in Vo could result from changes in the kinetics of the myosin heavy chain ATPase. Motility assay, however, showed no changes between CASM and SASM in the ability of the purified myosin molecule (SF1) to translocate a marker actin filament. On the other hand, we found that the state of activation of the ATPase by phosphorylation of smooth muscle myosin light chain (molecular mass 20,000 Da) was greater in the SASM. This would account for the increased Vo. Investigating the signalling pathway, we found that whereas [Ca2+]i increased in both isometric and isotonic contraction, there was no significant difference between CASM and SASM. The content and activity of calmodulin were also not different between the 2 muscles. Nevertheless, we did find that content and total activity of smooth muscle myosin light chain kinase (smMLCK) and the abundance of its message were greater; this would explain the increased MLC20 phosphorylation. The binding affinity between Ca2+ and calmodulin and between 4 Ca2+ calmodulin and smMLCK remains to be studied. We conclude that SASM shows increased isotonic shortening capacity and velocity. It also shows increased content and total activity of smMLCK, which is consistent with the increased shortening. Plasticity produced by oscillation is not seen in the shortening muscle, although it is seen with respect to force development. It did not modulate the behaviour of the sensitized muscle.

Isotonic relaxation of control and sensitized airway smooth muscle.

Smooth muscle relaxation has most often been studied in isometric mode. However, this only tells us about the stiffness properties of the bronchial wall and thus only about wall capacitative properties. It tells us little about airflow. To study the latter, which of course is the meaningful parameter in regulation of ventilation and in asthma, we studied isotonic shortening of bronchial smooth muscle (BSM) strips. Failure of BSM to relax could be another important factor in maintaining high airway resistance. To analyze relaxation curves, we developed an index of isotonic relaxation, t1/2(P, lCE), which is the half-time for relaxation that is independent of muscle load (P) and of initial contractile element length (lCE). This index was measured in curves of relaxation initiated at 2 s (normally cycling crossbridges) and at 10 s (latch-bridges). At 10 s no difference was seen for adjusted t1/2(P, lCE) between curves obtained from control and sensitized BSM, (8.38 +/- 0.92 s vs. 7.78 +/- 0.93 s, respectively). At 2 s the half-time was almost doubled in the sensitized BSM (6.98 +/- 0.01 s (control) vs. 12.74 +/- 2.5 s (sensitized)). Thus, changes in isotonic relaxation are only seen during early contraction. Using zero load clamps, we monitored the time course of velocity during relaxation and noted that it varied according to 3 phases. The first phase (phase i) immediately followed cessation of electrical field stimulation (EFS) at 10 s and showed almost the same velocity as during the latter 1/3 of shortening; the second phase (phase ii) was linear in shape and is associated with zero load velocity, we speculate it could stem from elastic recoil of the cells' internal resistor; and the third phase (phase iii) was convex downwards. The zero load velocities in phase iii showed a surprising spontaneous increase suggesting reactivation of the muscle. Measurements of intracellular calcium (Fura-2 study) and of phosphorylation of the 20 kDa myosin light chain showed simultaneous increments, indicating phase iii represented an active process. Studies are under way to determine what changes occur in these 3 phases in a sensitized muscle. And of course, in the context of this conference, just what role the plastic properties of the muscle play in relaxation requires serious consideration.

Stretch-induced changes in constricted lung parenchymal strips: role of extracellular matrix.

Large amplitude oscillations of contracted airway smooth muscle cause relative relaxation of the preparation. However, little is known about the effect of mechanical stretch on distal lung behaviour. Rat parenchymal strips were suspended in an organ bath and attached at one end to a force transducer and at the other end to a servo-controlled lever arm that effected length changes. Mechanical impedance of the strip was measured by applying a complex signal consisting of pseudorandom length oscillations of varying frequencies (0.5-19.75 Hz). A constant phase model was fit to changes in length and tension to calculate tissue damping (G) and elastance (H). Hysteresivity was calculated as G/H. Impedance was measured before and after sinusoidal length oscillation at different amplitudes (1, 3, 10 and 25% of resting length) at a frequency of 1 Hz under baseline conditions and after acetylcholine-induced constriction. Oscillations of 10 and 25% amplitudes significantly decreased the G and H of the lung strip. The effect of length oscillations was no different in control versus constricted strips. These data suggest that in the distal lung, large stretches affect the structural components of the extracellular matrix rather than the contractile elements.

Changes in tear protein pattern after photorefractive keratectomy.

PURPOSE: Changes in tear protein composition of patients who underwent photorefractive keratectomy (PRK) were analyzed. METHODS: Tear samples were obtained from 23 eyes of 23 patients immediately before PRK and on the fourth postoperative day with glass capillaries. Tear proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Digital image analysis and evaluation of the densitometric data of the electrophoretic separations were done with BioDoc-Analyze. RESULTS: Analysis of discriminance found a significant difference in the protein patterns (p < 0.001). This type of analysis of the electrophoretic densitographs uses all peak information simultaneously. A significant decrease (p < 0.005) in three of the main protein peaks--lactoferrin, immunoglobulin A heavy chain, and lysozyme--was also found after PRK. CONCLUSIONS: Excimer laser ablation of the cornea has an acute effect on lacrimal gland protein secretion. Changes in tear composition may lead to feelings of dryness and to a decrease in tear film stability postoperatively.

Photorefractive keratectomy for hyperopia in 800 eyes with the Meditec MEL 60 laser.

PURPOSE: To evaluate the refractive results of 800 hyperopic eyes undergoing PRK treatment. METHODS: Eight hundred hyperopic eyes were treated with PRK. An Aesculap-Meditec MEL 60 scanning ArF excimer laser used. Treatment Group 1 consisted of eyes with a preoperative refractive error of +3.50 D or less (n = 482) and Group 2, of +3.75 D or more (n = 318). RESULTS: Preoperatively, Group 1 required an average correction of +2.88+/-1.34 D and Group 2 required +5.64+/-2.96 D. One year after PRK, average residual correction was +1.26+/-1.24 D in Group 1, and in Group 2, +2.46+/-1.84 D. In Group 1, uncorrected visual acuity (UCVA) was 20/40 or better in 88.4% (426/482); 20/20 or better in 75.7% (365); 2.1% (10/482) of eyes lost 2 lines, 2.1% (10/482) gained 2 lines; 3.1% (15/482) gained 2 or more lines of BSCVA; 74.4% (359/482) of eyes were within +/-0.50 D of target correction and 84.8% (408/482) were within +/-1.00 D. In Group 2, 47.5% (151/318) had UCVA of 20/40 or better; 34.2% (109/318) saw 20/20 or better uncorrected; 19.1% (61/318) lost 2 lines; 11.6% (37/318) lost 3 lines; none of the eyes gained 2 or more lines of BSCVA; 22.3% (71/318) were within +/-0.50 D and 46.8% (149/318) were within +/-1.00 D of target correction. Refractive stability was achieved after 6 months; a slight regression after 6 months was still observed. In Group 1, 10.5% (42/482) and in Group 2, 21.6% (69/318) complained of problems with daytime vision (glare and ghost image); during night-driving in Group 1, 17.6% (85/482) and in Group 2, 40.5% (129/318) had problems. CONCLUSION: PRK with the Aesculap-Meditec MEL 60 scanning ArF excimer laser offered the best long-term results with +3.50 D or less preoperative refractive error. With higher corrections, regression, decrease in BSCVA, and daytime visual problems were encountered.

[Results of photorefractive keratectomy after treatment of 2053 eyes]. / Az excimer lézeres fotorefraktív keratectomia tapasztalatai 2053 szem kezelése kapcsán.

To evaluate the 12 months refractive results of photorefractive excimer keratectomy (PRK) in high number of eyes with different type of refractive error. Between October 1992 and December 1996. 2053 eyes of 1098 patients were treated with the Aesculap Meditec MEL 60 argon-fluoride excimer laser. Refractive results were concluded at the 12th post-PRK month. The following patient groups were used during the study: Group 1.: Eyes between -1.0 D and -6.0 D (n = 651); Group 2.: -6.0 és -9.0 D (n = 216); Group 3.: Eyes with refractive error above -9.0 D (n = 163); Group 4.: Hypermetrop eyes (n = 160); Group 5.: Eyes with myopic astigmatism (n = 746); Group 6.: Eyes with hypermetropic astigmatism; Group 7.: Pure astigmatism (n = 13). In Group 1. The preoperative average -3.94 +/- 1.3 D refractive error decreased during the 1-year follow-up period to -0.47 +/- 0.54 Dpt; in Group 2. The preoperative -7.65 +/- 1.07 D to -1.16 +/- 1.86 D; in Group 3. The preoperative average -13.58 +/- 3.51 D to -3.11 +/- 2.75 D; in Group 4. The preoperative +4.04 +/- 1.77 D to +1.02 +/- 1.16 D in Group 5. The preoperative -6.06 +/- 2.78 D spherical component decreased to -0.95 +/- 1.33 D-ra, whereas the preoperative cylindrical component from -1.5 +/- 1.08 D to -0.13 +/- 0.58 D; in Group 5. The preoperative +4.57 +/- 1.78 spherical component to +1.13 +/- 1.38 D; whereas the preoperative cylindrical component from +1.57 +/- 0.96 D to +0.38 +/- 0.77 D; in Group 7. The preoperative a -3.98 +/- 1.2 D cylinder decreased to -0.62 +/- 0.75 D cylinder. PRK decreased effectively the preoperative correction need in every treatment group. The results are the better, the smaller the preoperative correction need is.

Excimer laser treatment of hyperopia.

PURPOSE: The aim of this study was to analyse the clinical results of hyperopic photorefractive keratectomy treatments and to compare the results achieved with the usage of different masks. METHOD: 20 eyes of 16 hyperopic patients were treated, using the Aesculap-Meditec MEL60 193nm ArF excimer laser. The mean duration of follow-up was 9.9+/-3.4 months. Statistical comparison of the results with the two masks was made using the unpaired Student t-test. RESULTS: Preoperative mean spherical equivalent was +4.23+/-1.18D, which changed to +0.20+/-0.78D at one month and regressed to +1.23+/-1.27D at the last control examination. After 6 months 60% (12 eyes) had spherical equivalent within +/-1.0D of the attempted correction. The statistical analysis showed no significant difference between the results with the two masks. CONCLUSION: Good preparation for the treatment is of equal importance for the results of the photorefractive keratectomy as compared to the technical circumstances.

[Phototherapeutic use of excimer laser]. / Az excimer lézer fototerápiás felhasználásáról.

The photorefractive excimer laser is not only able to alter the refractive power of the corneas but also suitable to treat superficial corneal pathologies. Authors performed phototherapeutic keratectomies (PTK) in 80 eyes of 77 patients. The age was on average (+/- S.D.) 49.4 +/- 22.03 years. The follow-up time varied between 3-24 months. All treatments were performed with the Aesculap Meditec MEL 60 ArF excimer laser, working in the 193 nm extreme ultraviolet-C range. Authors conclude that the best postoperative results can be achieved with PTK in cases of recurrent corneal erosions and superficial corneal opacities. Favourable outcome could be expected in treatment of infectious corneal ulcers. In cases of bullous keratopathy the subjective complaints decreased and it was successful to postpone the time of perforating keratoplasty. The PTK is not recommended in case of corneal Bowen disease and recurrent pterygia. A hyperopic shifts was observed in 2 eyes. Besides, the traditional surgical methods the phototherapeutic keratectomy is an important progress in treatment of superficial corneal pathologies. Applying the method, the recurrent erosions healed quicker, in most of the cases the transparency of the cornea could be reestablished in the pupillary area and the need for perforating keratoplasty could be postponed or avoided.

[Experience with excimer laser photorefractive keratectomy]. / Excimer lézeres fotorefraktív keratektomiák során szerzett tapasztalataink.

UNLABELLED: The correction of refractive errors based on superficial ablation of the cornea has a couple of years long history. Authors performed photorefractive laser surgery with the Aesculap Meditec MEL 60 ArF excimer laser in 221 eyes of 147 patients. The follow-up time varied between 2-24 months, average 8 months. They have treated the following groups: 1. group: 0-6.0 D; 2. group: -6.5-9.0 D; 3. group: eyes with refractive error above -9.5 D; 4. group: hypermetropic eyes; 5. group: eyes with astigmatism. RESULTS: In the 1. group the average -4.58 +/- 1.25 D refractive error decreased to -0.19 +/- 0.53 D in the follow-up time; 2. group: from -7.46 +/- 1.22 D to -0.45 +/- 0.83 D; 3. group: -13.76 +/- 5.46 D to -1.52 +/- 1.74; 4. group: +428 +/- 1.6 D to +0.91 +/- 2.41 D; 5. group; from -6.74 +/- 2.81 D sph -2.3 +/- 1.54 cyl to -0.51 +/- 1.3 D sph -0.54 +/- 1.06 D cyl. According to their experiences they conclude: the best results have been achieved in the first two groups and in eyes with astigmatism (1., 2., 5. groups). In severe myopia cases postoperative correction is usually needed, which is significantly smaller than the preoperative spherical correction. The method is able to change the refractive power of the cornea and provides an efficient alternative to the spectacles and contact lenses.

Retinoscopy after excimer laser photorefractive treatments.

Photorefractive keratectomy (PRK) is capable of changing the refractive power of the human cornea. Retinoscopy is an objective method of measuring the refractive power of the eye. The authors performed PRK in 28 myopic eyes with the Aesculap Meditec MEL 60 ArF excimer laser. During a prospective study, the subjective and objective refractive power of the eyes were assessed and compared 6 months after PRK. The average preoperative refractive error was: -5.11 +/- 2.51 D and -5.08 +/- 2.20 D on the right side (n = 16) and on the left side (n = 12), respectively. In order to obtain the best corrected visual acuity 6 months after PRK, the right and left eyes needed an average of -0.09 +/- 0.26 D and -0.33 +/- 0.64 D postoperative correction, respectively. The postoperative refractive change could be verified with the retinoscopy at +/-0.5 D accuracy. The authors describe a double refractive corneal ring after PRK, which may disturb retinoscopy. The post-PRK refractive change can be verified by retinoscopy. Postoperative funduscopy, fundus photography and possible future retinal procedures were not disturbed by the double corneal refractive rings in myopic eyes.

Refractive results after photorefractive excimer laser treatment in mild myopic and in mild hyperopic eyes.

Evaluation of 12-month results of photorefractive keratectomies (PRK) performed in low myopic (0 to -6.0 D) and low hyperopic (0 to +6.0 D) eyes. Myopic and hyperopic PRK treatments with the Aesculap Meditec MEL 60 ArF excimer laser. Prospective study, 30 eyes per group. The change in best corrected visual acuity (VA), refraction required, uncorrected VA and the postoperative haze were compared at the 12th postoperative month. The average preoperative correction in the low myopic eyes (Group I) was -4.65 +/- 1.24 D, which decreased to -0.17 +/- 0.56 D during the follow-up. In mild hyperopic eyes (Group II) the preoperative refraction was +3.9 +/- 0.93 D and decreased to +1.23 +/- 1.59 D post-PRK. Comparing the pre- and postoperative average best corrected VA values, there was no statistical change in either group. In the low myopic group all eyes had a 20/40 or better uncorrected VA, in hyperopic eyes 11 had a VA of 20/40 or better, four had a worse uncorrected VA. In Group I, 86.6% of the eyes were within +/-1.0 D of the intended refraction at 12 months postoperatively. In Group II, 46.7% of the eyes were within +/-1.0 D of final refraction. There were no intergroup differences in subjective complaints, reepithelization and average postoperative haze. Both methods are able to alter the refractive power of the cornea toward emmetropia. The predictability of the method was to be found higher in cases of mild myopia than in mild hyperopia. The upper limit of myopia is above -6.0 D, but in hyperopia, with the present technical facilities, good postoperative results can be obtained only as far as +4.25 D of preoperative refractive error.

Experiences with photorefractive excimer laser treatment in compound myopic astigmatism.

The invention of excimer lasers and different masks in order to treat refractive failures has opened a new era in refractive surgery. The refractive grading, the ablation effect, which can be controlled within one micrometer, and the design of a special mask made possible so-called "corneal sculpting" in compound astigmatism. The authors evaluated their experiences on 27 myopic compound astigmatic eyes. The average age of the patients was 28.67 +/- 9.78 years and the average preoperative uncorrected visual acuity was 0.06 +/- 0.04. The spherical component averaged -6.74 +/- 2.81 D and the cylindrical component averaged -2.3 +/- 1.54 D (the preoperative correction needed to obtain the best corrected visual acuity). Postoperatively, the uncorrected visual acuity improved to 0.65 +/- 0.26. To obtain the best corrected postoperative visual acuity an average -0.51 +/- 1.06 D sph and an average -0.54 +/- 1.06 D cyl component was needed. The authors conclude that ArF excimer laser treatment is able to alter both of the spherical and cylindrical components of the eye toward emmetropia. The lower the degree of preoperative compound myopic astigmatism, the better are the chances of postoperative emmetropia. No serious complications were met during the follow-up period.

The surgical correction of refractive errors of the eye.

Authors review the available surgical methods, the radial keratotomy, the keratophakia, the keratomileusis, the epikeratophakia and the excimer laser technique which are available presently in order to change the refractive power of the eye. The newest excimer technique is discussed in detail. During the past one and a half year period authors performed and closely followed 37 photorefractive keratectomies with the use of Aesculap Meditec MEL 60 excimer laser. They present the postoperative results, according to their experiences, the method is highly effective and predictable in treating myopic refractive failures. The side effects were of no clinical importance.

Plume emission, shock wave and surface wave formation during excimer laser ablation of the cornea.

Excimer lasers are now used for corneal surgery; however, the physical processes occurring during photoablation of the cornea are incompletely understood. High speed laser-based photographic arrangement was constructed. The temporal resolution was better than 1 ns. The setup could work as a Schlieren arrangement, which is sensitive to the refractive index change caused by the shock wave propagating in the air above the eye. With minor changes the setup was converted into a shadowgraph, which could detect the ablation plume and the waves propagating on the surface of the eye. Due to the impact of the excimer laser pulse onto the surface of the cornea, a shock wave was generated in the air. The shadowgraph clearly showed the ejection of the ablated cornea. The ejection velocity of the plume was found to be over 600 m/s. It was shown for the first time that the recoil forces of the plume are generating a wave on the surface of the eye. The laser-based high speed photographic arrangement is a powerful arrangement in the study of physical effects occurring during photoablation of the cornea.