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(Chest. 2002;121:621-624.)
© 2002 American College of Chest Physicians

Airway Hyperresponsiveness and Calcium Handling by Smooth Muscle*

A "Deeper Look"

Krishnan Parameswaran, MD, FCCP; Luke J. Janssen, PhD and Paul M. O’Byrne, MB, FCCP

* From the Asthma Research Group, Department of Medicine, St. Joseph’s Healthcare & McMaster University, Hamilton, ON, Canada.

Correspondence to: Paul M. O’Byrne, MB, FCCP, Firestone Institute for Respiratory Health, St. Joseph’s Healthcare, 50 Charlton Ave East, Hamilton, ON L8N 4A6, Canada; e-mail: obyrnep{at}mcmaster.ca


   Abstract
TOP
 Abstract
Introduction
 References
 
We propose that abnormal calcium handling by the airway smooth muscle may be an important determinant of airway hyperresponsiveness. The amplitude, frequency, or localization of Ca2+ oscillations in the smooth muscle may determine the degree of airway sensitivity and reactivity, which are characteristic features of asthma.

Key Words: airway hyperresponsiveness • airway smooth muscle • asthma • calcium


   Introduction
TOP
 Abstract
 Introduction
References
 
Airway hyperresponsiveness (AHR) is a characteristic feature of asthma, and its measurement is an important tool in its diagnosis.1 2 The term AHR describes two important properties of the airways of an asthmatic patient, hypersensitivity and hyperreactivity.3 These terms have distinct pharmacologic meanings. Hypersensitivity reflects a lower threshold response to an agonist, while hyperreactivity reflects a steeper dose-response relationship and often a higher maximal response.4 Despite decades of intense research, the underlying mechanisms of AHR remain unclear. Multiple factors, including genetic inheritance, atopy, resting airway caliber, and cells and mediators of airway inflammation, have been implicated in causing AHR.5 Abnormal calcium handling by the airway smooth muscle (ASM) leading to an increase in intracellular calcium ([Ca2+]i) was considered to be responsible for AHR.6 However, the lack of clinically relevant attenuation of AHR by voltage-dependent calcium channel-blocking drugs.7 8 suggested that [Ca2+]i may not be important in determining AHR. The emphasis then shifted to the presence of airway inflammation, in particular eosinophil infiltration of the airway mucosa, in the development of AHR. This dogma is changing.9 Recent observations10 of the lack of improvement in AHR despite significant attenuation of eosinophil numbers with specific treatment directed against proinflammatory cytokines suggest that cellular inflammation may not be the only determinant of AHR.

Focus has returned to the role of the ASM in determining the degree of AHR.11 This may be related to the viscoelastic and plastic properties of the ASM12 or, alternatively, to the interaction of the ASM with the extracellular matrix.13 The hypertrophy and/or hyperplasia of the ASM, which often is seen in airways of asthmatic patients,14 may be responsible for the greater force of contraction.15 An increase in muscle-shortening velocity may be due to an increase in activity of the enzyme myosin light chain kinase.16 These mechanisms can be used to explain diverse phenomena in the airways of asthmatic patients such as the generation of greater isometric force of contraction, abnormal relaxation, and the relaxant effect of muscle stretch. While these theories offer a satisfactory explanation for the hyperreactivity of the airways (ie, excessive airway narrowing), they do not provide a convincing interpretation for the hypersensitivity of the airways.

What is it that makes the ASM inherently hypersensitive and hyperreactive? We propose that it is primarily due to an altered state of calcium handling by the ASM.17 Calcium is involved in all the key steps of smooth muscle contraction and relaxation.18 Indeed, the [Ca2+]i levels in single-passage ASM cells are higher in inbred hyperresponsive Fisher rats than in the less responsive Lewis rats.19 Since various diverse excitatory stimuli, such as leukotrienes,20 acetylcholine,21 ozone,22 acroleins,23 tumor necrosis factor-{alpha},24 and the inflammatory cell activation product major basic protein,25 provoke AHR by mobilizing [Ca2+]i, it is conceivable that the calcium handling in the smooth muscle per se is altered. Recent advances in our understanding of the regulation of [Ca2+]i levels and the propagation of calcium signals in waveforms may be important to understand smooth muscle hyperresponsiveness.

Traditionally, it has been thought that an agonist-induced smooth muscle contraction is associated with an increase of, and a relaxation with a decrease of, [Ca2+]i. The process, however, may not be that simple. Just as in the vascular smooth muscle,26 a superficial buffer barrier that is formed by sheets of sarcoplasmic reticulum has been described in ASM.27 This divides the cytosol into a superficial subplasmalemmal space and a deep cytosolic space. Spasmogens release Ca2+ into the deep cytosol, which triggers contraction, but also into the superficial subplasmalemmal space, which activates the calcium-dependent chloride channels, causing membrane depolarization and voltage-dependent calcium influx. Relaxants have been shown to elevate subplasmalemmal Ca2+ concentration, but decrease it in the deep cytosol.28 29 Thus, whereas the subplasmalemmal Ca2+ level predominantly determines membrane current, the deep cytosolic Ca2+ level determines smooth muscle contraction. Global measurement of [Ca2+]i do not reflect this spatial heterogeneity. Precisely for the same reason, previous experiments using drugs that block the voltage-activated calcium channels and regulate the [Ca2+]i in the superficial cytosol may have had little effect on ASM contraction and AHR. The specific contribution of deep cytosolic Ca2+ in the ASM to AHR has not been examined. We speculate that the smooth muscle of patients with asthma may have a greater proportion of the internal Ca2+ compartmentalized in the deep cytosol than that of individuals without asthma, thereby making the ASM hypercontractile to an array of stimulants, cytokines, and inflammatory mediators.30 It may also be possible that an airway inflammatory process facilitates a shift of [Ca2+]i from the superficial to the deep cytosolic space, thereby increasing the maximal airway narrowing observed in patients with asthma.

Perhaps an even more relevant determinant of AHR is the characteristics of cytoplasmic and nuclear waveforms of calcium oscillations, which are increasingly recognized as fundamental in regulating many cellular functions in both excitable and nonexcitable cells.31 32 Cytosolic Ca2+ signals often are organized in complex temporal and spatial patterns, reflecting the complex regulation of the release of internal calcium.33 This is predominantly controlled by two receptors on the sarcoplasmic reticulum. Most endogenous spasmogens act through receptors that are coupled to phospholipase C, which metabolizes the membrane lipid phosphatidyl inositol phosphate leading to the generation of the second messenger inositol trisphosphate (IP3). The second group of receptors regulates calcium-permeable channels that open in response to an elevation of the cytosolic calcium concentration. They amplify calcium release through the IP3-gated channels. These channels can also be activated by ryanodine, a plant-derived, muscle-paralyzing alkaloid, and therefore they are often referred to as ryanodine receptors.

Oscillations of cytosolic [Ca2+]i, which reflect the opening and closing of IP3 and ryanodine receptor-activated channels, may take the form of [Ca2+]i waves that propagate throughout the cell, or they may be restricted to specific subcellular regions. In addition, the spatial organization of [Ca2+]i changes appears to depend on the strategic distribution of Ca2+ stores within the cell. One type of [Ca2+]i oscillation is baseline spiking, a condition in which discrete [Ca2+]i spikes of uniform amplitude occur with a frequency that is determined by the agonist dose. Sinusoidal [Ca2+]i oscillations represent a mechanistically distinct type of temporal organization, in which the agonist dose regulates the amplitude but has no effect on oscillation frequency. The individual cell may utilize Ca2+/calmodulin kinase II to decode the amplitude-modulated or frequency-modulated signals,34 which may have different effects on various critical steps of the inflammatory process.35 For example, Dolmetsch et al36 demonstrated a role for the amplitude and frequency of [Ca2+]i oscillation in regulating gene expression that is driven by the proinflammatory transcription factors NF-AT, Oct/OAP, and NF-{kappa}B, which are thought to be critical in regulating airway inflammation in patients with asthma.37 Oscillations reduced the effective [Ca2+]i threshold for activating transcription factors, thereby increasing signal detection at low levels of stimulation. In addition, rapid oscillations stimulated all three transcription factors, whereas infrequent oscillations activated only NF-{kappa}B. The genes encoding the cytokines interleukin-2 and interleukin-8 were also frequency-sensitive in a way that reflected their degree of dependence on NF-AT vs NF-{kappa}B. Ca2+ oscillation also may determine the physiologic response of mast cells and eosinophils to an antigenic challenge38 and the survival of inflammatory cells by its effect on Bcl-2.39 The specificity of Ca2+ oscillations also have been demonstrated in ASM. For example, the amplitude, but not the frequency of Ca2+ oscillations in isolated human ASM were dependent on arachidonic acid concentration.40 In freshly isolated myocytes from rat trachea exposed to acrolein, the amplitude and the frequency of Ca2+ oscillations showed different responses to increasing doses of acetylcholine.23

Thus, differences in the amplitude, frequency, or localization of Ca2+ oscillations may determine the degree of airway responsiveness, which characterizes an asthmatic airway, just as the spatiotemporal properties of the calcium oscillations may determine the arrhythmogenicity of the cardiac muscle.41 Frequency modulation of calcium waves may make the airways hypersensitive. Anti-inflammatory drugs like corticosteroids and leukotriene antagonists, which decrease the expression of transcription factors, may alter the frequency and amplitude of the calcium waves and thereby shift the threshold response to contractile agonists. Although they decrease the level of global [Ca2+]i in response to a contractile agonist,42 they may not have a significant effect on the distribution of calcium between the superficial and deep cytosolic space. Therefore, the slope of airway reactivity and the maximal response may not be significantly altered (Fig 1 ). The decrease in airway sensitivity and reactivity43 and in the maximum shortening velocity of the ASM44 with aging may be related to the concurrent changes in the frequency and amplitude of calcium oscillations in the ASM.39 With advances in technology, such as the confocal laser or multiphoton scanning microscopy and digital video fluoroscopy, it is now possible to visualize and measure the elementary events that constitute the global Ca2+ signals and to test these hypotheses.



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  		Figure 1. Theoretical construct of abnormal calcium handling of ASM and AHR. Top left, A: airway hypersensitivity shown as a shift to the left of the dose-response curve of agonist-induced contraction. Bottom left, B: waves of intracellular calcium release by the activation of IP3 receptors and ryanodine receptors on the sarcoplasmic reticulum of asthmatic ASM. The waves may have varying frequencies and amplitudes, which may affect the regulation of transcription factors and the threshold of agonist-induced contraction. Higher frequency or amplitude may shift the dose-response curve to the left. Top right, C: airway reactivity shown as a steeper slope and greater response to agonist-induced contraction. Bottom right, D: asthmatic airway smooth muscle with a greater proportion of intracellular calcium in the deep cytosolic space compared to the superficial subplasmalemmal space. The deep cytosolic calcium leads to more airway narrowing.

 


   Acknowledgements
 
We thank Dr. P. G. Cox, McMaster University, for reviewing the manuscript.


   Footnotes
 
Abbreviations: AHR = airway hyperresponsiveness; ASM = airway smooth muscle; [Ca2+]i = intracellular calcium; IP3 = inositol trisphosphate

Dr. Parameswaran is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research.

Received for publication June 21, 2001. Accepted for publication August 21, 2001.


   References
TOP
 Abstract
 Introduction
 References
 

  1. Hargreave, FE, Ryan, G, Thomson, NC, et al (1981) Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. J Allergy Clin Immunol 68,347-355[CrossRef][ISI][Medline]
  2. Lotvall, J, Inman, M, O’Byrne, P (1998) Measurement of airway hyperresponsiveness: new considerations. Thorax 53,419-424[Free Full Text]
  3. Sterk, PJ, Bel, EH (1989) Bronchial hyperresponsiveness: the need for a distinction between hypersensitivity and excessive airway narrowing. Eur Respir J 2,267-274[Abstract]
  4. Woolcock, AJ, Salome, CM, Yan, K (1984) The shape of the dose-response curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis 130,71-75[ISI][Medline]
  5. Hargreave, FE, Dolovich, J, O’Byrne, PM, et al (1986) The origin of airway hyperresponsiveness. J Allergy Clin Immunol 78,825-832[CrossRef][ISI][Medline]
  6. Triggle, DJ (1983) Calcium, the control of smooth muscle function and bronchial hyperreactivity. Allergy 38,1-9[ISI][Medline]
  7. Henderson, AF, Costello, JF (1988) The effect of nifedepine on bronchial reactivity to inhaled histamine and methacholine: a comparative study in normal and asthmatic subjects. Br J Dis Chest 82,374-381[CrossRef][ISI][Medline]
  8. Fish, JE, Norman, PS (1986) Effects of the calcium channel blocker, verapamil, on asthmatic airway responses to muscarinic, histaminergic, and allergenic stimuli. Am Rev Respir Dis 133,730-734[ISI][Medline]
  9. Brusasco, V, Crimi, E, Pellegrino, R (1998) Airway hyperresponsiveness in asthma: not just a matter of airway inflammation. Thorax 53,992-998[Free Full Text]
  10. Leckie, MJ, ten Brinke, A, Khan, J, et al (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356,2144-2148[CrossRef][ISI][Medline]
  11. Solway, J, Fredberg, JJ (1997) Perhaps airway smooth muscle dysfunction contributes to asthmatic bronchial hyperresponsiveness after all. Am J Respir Cell Mol Biol 17,144-146[Free Full Text]
  12. Martin, JG, Duguet, A, Eidelman, DH (2000) The contribution of airway smooth muscle to airway narrowing and airway hyperresponsiveness in disease. Eur Respir J 16,349-354[Abstract]
  13. Gunst, SJ, Tang, DD (2000) The contractile apparatus and mechanical properties of airway smooth muscle. Eur Respir J 15,600-616[Abstract]
  14. Ebina, M, Yaegashi, H, Chiba, R, et al (1990) Hyperreactive site in the airway tree of asthmatic patients revealed by thickening of bronchial muscles. Am Rev Respir Dis 141,1327-1332[ISI][Medline]
  15. Lambert, RK, Wiggs, BR, Kuwano, K, et al (1993) Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 74,2771-2781[Abstract/Free Full Text]
  16. Ammit, AJ, Armour, CL, Black, JL (2000) Smooth muscle myosin light chain kinase content is increased in human sensitized airways. Am J Respir Crit Care Med 161,257-263[Abstract/Free Full Text]
  17. Janssen, LJ (1998) Calcium handling in airway smooth muscle: mechanisms and therapeutic implications. Can Respir J 5,491-498[Medline]
  18. Horowitz, A, Menice, CB, Laporte, R, et al (1996) Mechanisms of smooth muscle contraction. Physiol Rev 76,967-1003[Abstract/Free Full Text]
  19. Tao, FC, Tolloczko, B, Eidelman, DH, et al (1999) Enhanced Ca2+ mobilization in airway smooth muscle contributes to airway hyperresponsiveness in an inbred strain of rat. Am J Respir Crit Care Med 160,446-453[Abstract/Free Full Text]
  20. Dumitriu, D, Prie, S, Bernier, SG, et al (1997) Mechanism of action of leukotriene D4 on guinea pig tracheal smooth muscle cells: roles of Ca++ influx and intracellular Ca++ release. J Pharmacol Exp Ther 280,1357-1365[Abstract/Free Full Text]
  21. Janssen, LJ, Sims, SM (1993) Emptying and refilling of Ca2+ stores in tracheal myocytes as indicated by Ach-evoked currents and contraction. Am J Physiol 265,C877-C886[Abstract/Free Full Text]
  22. Montano, LM, Jones, GL, O’ Byrne, PM, et al (1993) Effect of ozone exposure in vivo on response of bronchial rings in vitro: role of intracellular Ca2+. J Appl Physiol 75,1315-1322[Abstract/Free Full Text]
  23. Roux, E, Hyvelin, J-M, Savineau, J-P, et al (1998) Calcium signalling in airway smooth muscle cells is altered by in vitro exposure to aldehyde acrolein. Am J Respir Cell Mol Biol 19,437-444[Abstract/Free Full Text]
  24. Parris, JR, Cobban, HJ, Littlejohn, AF, et al (1999) Tumour necrosis factor-{alpha} activates a calcium sensitization pathway in guinea-pig bronchial smooth muscle. J Physiol 518,561-569[Abstract/Free Full Text]
  25. Wylam, ME, Gungor, N, Mitchell, RW, et al (1998) Eosinophils, major basic protein, and polycationic peptides augment bovine airway myocyte Ca2+ mobilization. Am J Physiol 274,L997-L1005[Abstract/Free Full Text]
  26. Van Breemen, C, Chen, Q, Laher, I (1995) Superficial buffer barrier function of smooth muscle sarcoplasmic reticulum. Trends Pharmacol Sci 16,98-105[CrossRef][Medline]
  27. Janssen, LJ, Betti, PA, Netherton, SJ, et al (1999) Superficial buffer barrier and preferentially directed release of Ca2+ in canine airway smooth muscle. Am J Physiol 276,L744-L753[Abstract/Free Full Text]
  28. Yamaguchi, H, Kakita, J, Madison, JM (1995) Isoproterenol increases peripheral [Ca2+]i and decreases inner [Ca2+]i in single airway smooth muscle cells. Am J Physiol 268,C771-C779[Abstract/Free Full Text]
  29. Janssen, LJ, Premji, M, Lu-Chao, H, et al (2000) NO+ but not NO radical relaxes airway smooth muscle via cGMP-independent release of internal Ca2+. Am J Physiol 278,L899-L905
  30. Amrani, Y, Panettieri, RA, Jr (1998) Cytokines induce airway smooth muscle cell hyperresponsiveness to contractile agonists. Thorax 53,713-716[Free Full Text]
  31. Rottingen, JA, Iversen, JG (2000) Ruled by waves? Intracellular and intercellular calcium signaling. Acta Physiol Scand 169,203-219[CrossRef][ISI][Medline]
  32. Bootman, MD, Thomas, D, Tovey, SC, et al (2000) Nuclear calcium signalling. Cell Mol Life Sci 57,371-378[CrossRef][Medline]
  33. Thomas, D, Lipp, P, Tovey, SC, et al (2000) Microscopic properties of elementary Ca2+ release sites in non-excitable cells. Curr Biol 10,8-15[CrossRef][ISI][Medline]
  34. Dupont, G, Goldbeter, A (1998) CaM kinase II as frequency decoder of Ca2+ oscillations. Bioessays 20,607-610[CrossRef][ISI][Medline]
  35. Berridge, MJ (1997) The AM and FM of calcium signalling. Nature 386,759-780[CrossRef][Medline]
  36. Dolmetsch, RE, Xu, K, Lewis, RS (1998) Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392,933-936[CrossRef][Medline]
  37. Barnes, PJ, Adcock, IM (1998) Transcription factors and asthma. Eur Respir J 12,221-234[Abstract]
  38. Narenjkar, J, Marsh, SJ, Assem, ESK (1999) The characterization and quantification of antigen-induced Ca2+ oscillations in a rat basophilic leukaemia cell line (RBL-2H3). Cell Calcium 26,261-269[CrossRef][ISI][Medline]
  39. Berridge, MJ, Bootman, MD, Lipp, P (1998) Calcium: a life and death signal. Nature 395,645-648[CrossRef][Medline]
  40. Durand, J, Marmy, N (1994) Arachidonic acid induces [Ca2+]i oscillations in smooth muscle cells from human airways. Respir Physiol 97,249-261[CrossRef][ISI][Medline]
  41. Stuyvers, BD, Boyden, PA, ter Keurs, HEDJ (2000) Calcium waves: physiological relevance in cardiac function. Circ Res 86,1016-1018[Free Full Text]
  42. Tanaka, H, Watanabe, K, Tamura, N, et al (1995) Arachidonic acid metabolites and glucocorticoid regulatory mechanism in cultured porcine tracheal smooth muscle cells. Lung 173,347-361[ISI][Medline]
  43. Montgomery, GL, Tepper, RS (1990) Changes in airway reactivity with age in normal infants and young children. Am Rev Respir Dis 142,1372-1376[ISI][Medline]
  44. Chitano, P, Wang, J, Cox, CM, et al (2000) Different ontogeny of rate of force generation and shortening velocity in guinea pig trachealis. J Appl Physiol 88,1338-1345[Abstract/Free Full Text]



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