Location, location, location: microlocalisation of inflammatory cells and airway dysfunction
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《胸》
Institute for Lung Health, University of Leicester, Division of Respiratory Medicine, Leicester, UK
Correspondence to:
Dr I D Pavord
Institute for Lung Health, Department of Respiratory Medicine, University Hospitals of Leicester, Groby Road, Leicester LE3 9QP, UK; ian.pavord@uhl-tr.nhs.uk
Role of inflammatory cell location in the pathogenesis of asthma, COPD, and cough
Keywords: inflammatory cells; microlocalisation; asthma; chronic obstructive pulmonary disease
Most inflammatory mediators are rapidly inactivated once they leave the cell so that they act across distances of only a few microns. It is therefore likely that microlocalisation between inflammatory and structural cells is a fundamental organising principle of airway inflammation and repair.
Enthusiasm for the view that microlocalisation is important in obstructive airway diseases has been fuelled by studies which showed inflammatory cells within the airway smooth muscle in asthma and chronic obstructive pulmonary disease (COPD) but not in normal controls. In asthma the airway smooth muscle is infiltrated by mast cells, predominantly of the chymase positive phenotype. Mast cell numbers correlate inversely with airway responsiveness,1 which suggests that interactions between mast cells and smooth muscle cells are central in the development of the disordered physiology in asthma. The strength of this assertion is underpinned by the paucity of mast cells within the airway smooth muscle in eosinophilic bronchitis, a condition that presents with chronic cough and shares many of the immunopathological features of asthma but is not associated with airflow obstruction or airway hyperresponsiveness.1–3 Importantly, there is evidence that mast cells infiltrating the airway smooth muscle bundle are activated; a necroscopic study of fatal and non-fatal asthma has shown that there is a marked increase in mast cell degranulation in the airway smooth muscle in both the large and small airways.4
A recent study has investigated whether a similar phenomenon occurs in COPD. Baraldo et al5 found increased numbers of neutrophils and CD8+ cells—but not mast cells—in the small airways of smokers with COPD, and the neutrophil number was inversely related to percentage predicted forced expiratory volume in 1 second (FEV1). This is consistent with an earlier study which showed that the number of neutrophils in the airway smooth muscle in smokers is related to air trapping as determined by CT scanning.6 However, in this study Berger et al found that the number of chymase positive mast cells was more closely related with air trapping. Most of the subjects in these studies had undergone lung resection for cancer so, although the airways studied were considered to be from unaffected areas, there remains the possibility that the underlying lung cancer contributed to the inflammatory changes. Nevertheless, the body of evidence strongly suggests that microlocalisation of inflammatory cells within the airway smooth muscle bundle is an important feature of obstructive airway diseases. This raises two key questions:
Why do specific inflammatory cells accumulate in the airway smooth muscle in asthma and COPD?
How do interactions between these inflammatory cells and airway smooth muscle cells lead to disordered airway function?
WHY DO SPECIFIC INFLAMMATORY CELLS ACCUMULATE IN THE AIRWAY SMOOTH MUSCLE IN ASTHMA AND COPD?
Selective recruitment of inflammatory cells to the airway smooth muscle is likely to be mediated by smooth muscle derived chemoattractants and by maintenance of the correct microenvironment to maintain cell differentiation and survival. Airway smooth muscle has a significant secretory capacity, so it clearly has the potential to recruit inflammatory cells.7 For example, CXCL8 (IL-8) and CXCL10 (IP-10) released by activated airway smooth muscle in COPD may mediate neutrophil and CD8+ cell migration into the airway smooth muscle bundle.8,9 A plethora of chemotactic factors for mast cells are released by airway smooth muscle—notably, stem cell factor (SCF),10 CCL11 (eotaxin),11 CXCL8 (IL-8),8 and transforming growth factor (TGF)-?.10 We have recently shown that CXCR3 is the most abundantly expressed chemokine receptor on human lung mast cells within airway smooth muscle, that human lung mast cell migration is induced by the CXCR3 ligand CXCL10, and that CXCL10 is released preferentially from asthmatic airway smooth muscle cells compared with those from healthy controls.12 Future studies investigating the effects of inhibiting this pathway will be of particular interest.
It is likely that a number of other chemokines play a role in the recruitment of inflammatory cells into the airway and it may be that the release of chemotaxins by airway smooth muscle varies in response to different stimuli such as cigarette smoke, infection, or allergen exposure. Future studies should explore the relative importance of these triggers and the associated chemotaxins that are released in promoting inflammatory cell infiltration into the airway smooth muscle. It is also important to investigate why some inflammatory cells, notably eosinophils, are rarely seen in the airway smooth muscle in spite of appropriate chemotactic signals.
HOW DO INTERACTIONS BETWEEN THESE INFLAMMATORY CELLS AND AIRWAY SMOOTH MUSCLE CELLS LEAD TO DISORDERED AIRWAY FUNCTION?
Activation of the inflammatory cells within the airway smooth muscle bundle would be predicted to have important consequences on airway smooth muscle function. Following mast cell degranulation the mediators histamine, PGD2 and LTC4 are released which are all potent agonists for airway smooth muscle contraction.13 Mast cell cytokines may further contribute to airway hyperreponsiveness. The mast cells in the airway smooth muscle bundles in asthma express IL-13,14 and IL-13 has been shown to attenuate relaxation to ? agonists and to augment contractility to acetylcholine.15,16 The effect of neutrophil derived mediators on airway smooth muscle function is less clear, with conflicting reports from animal studies showing that elastase can increase and diminish smooth muscle responsiveness.17,18
The interactions between inflammatory cells and airway smooth muscle cells may have more long term consequences. A number of mast cell mediators including histamine,19 tryptase,20 and LTD4,21 as well as the neutrophil product elastase,22 promote airway smooth muscle proliferation. Increased airway smooth muscle mass is a well established feature of both asthma23 and COPD.24 In asthma this occurs predominantly in the large airway and in COPD in the small airways. A study using a computational model of the effects of increased muscle mass has suggested that it is the most important abnormality responsible for the increased airflow resistance observed in response to bronchoconstricting stimuli in both asthma and COPD.25 The relative contribution of airway wall smooth muscle mass to overall airway wall thickness in the small airways is much greater than that in the large airways. Thus, increased smooth muscle mass in the small airways is likely to make a significant contribution to the development of fixed airflow obstruction characteristic of COPD and sometimes seen in persistent chronic severe asthma. The role of interactions between inflammatory cells and smooth muscle cells in the development of airway wall remodelling in asthma and COPD offers exciting opportunities for future research.
FUTURE STUDIES
The recognition of the importance of microlocalisation is not confined to inflammatory cells and airway smooth muscle cells but is probably equally critical in interactions with other structural cells such as the epithelium, fibroblasts, mucosal glands, and nerve cells. Eosinophilic bronchitis, cough variant asthma, and idiopathic chronic cough are associated with increased concentration of mast cell products in sputum,26,27 and we have suggested that localisation of mast cells to sensory nerve endings might be important in the development of cough reflex hypersensitivity and cough. A rather similar interaction is thought to be important in the genesis of itch.28,29 Understanding the fundamental steps that are involved in the migration of inflammatory cells towards structural cells such as the airway smooth muscle and the interactions between these cells may provide us with novel targets for the future treatment of asthma, COPD, and cough. Researchers interested in the immunopathology of airway diseases therefore need to be mindful of the importance of "location, location, location".
REFERENCES
Brightling CE, Bradding P, Symon FA, et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002;346:1699–705.
Brightling CE, Ward R, Goh KL, et al. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med 1999;160:406–10.
Brightling CE, Symon FA, Birring SS, et al. Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax 2003;58:528–32.
Carroll NG, Mutavdzic S, James AL. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur Respir J 2002;19:879–85.
Baraldo S, Turato G, Badin C, et al. Neutrophilic infiltration within the airway smooth muscle in patients with COPD. Thorax 2004;59:308–12.
Berger P, Laurent F, Begueret H, et al. Structure and function of small airways in smokers: relationship between air trapping at CT and airway inflammation. Radiology 2003;228:85–94.
Knox AJ, Pang L, Johnson S, et al. Airway smooth muscle function in asthma. Clin Exp Allergy 2000;30:606–14.
John M, Au BT, Jose PJ, et al. Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2 cytokines and corticosteroids. Am J Respir Cell Mol Biol 1998;18:84–90.
Hardaker EL, Bacon AM, Carlson KA, et al. Regulation of TNF-- and IFN--induced CXCL10 expression: participation of the airway smooth muscle in the pulmonary inflammatory response in chronic obstructive pulmonary disease. FASEB J 2004;18:191–3.
Berger P, Girodet O, Begueret H, et al. Tryptase-stimulated human airway smooth muscle cells induce cytokine synthesis and mast cell chemotaxis. FASEB J 2003;17:2139–41.
Hirst SJ, Hallsworth MP, Peng O, et al. Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1? and is mediated by the interleukin-4 receptor -chain. Am J Respir Crit Care Med 2002;165:1161–71.
Brightling CE, Ammitt AJ, Berger P, et al. CXCL10 (IP-10) is a novel mast cell chemokine and is released by asthmatic airway smooth muscle (abstract). Thorax 2003;58 (Suppl III):iii4–5.
Brightling CE, Bradding P, Pavord ID, et al. New insights into the role of the mast cell in asthma. Clin Exp Allergy 2003;33:550–6.
Brightling CE, Symon FA, Holgate ST, et al. Interleukin-4 and -13 expression is co-localized to mast cells within the airway smooth muscle in asthma. Clin Exp Allergy 2003;33:1711–6.
Grunstein MM, Hakonarson H, Leiter J, et al. IL-13 dependent autocrine signalling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2002;282:520–8.
Laporte JC, Moore PE, Baraldo S, et al. Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med 2001;164:141–8.
Gray PR, Mitchell HW. Intramural elastase injection increases responsiveness of isolated bronchial segments. Pulm Pharmacol 1996;9:239–43.
Christensen GC, Lev A, Ryan J, et al. Rabbit trachealis tension responses to receptor-mediated agonists are diminished by elastase. Am J Respir Cell Mol Biol 1992;6:498–503.
Panettieri RA Jr, Yadvish PA, Kelly AM, et al. Histamine stimulates proliferation of airway smooth muscle and induces c-Fos expression. Am J Physiol 1990;259:L365–71.
Berger P, Perng DW, Thabrew H, et al. Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle. J Appl Physiol 2001;91:1372–9.
Espinosa K, Bosse Y, Stankova J, et al. CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4. J Allergy Clin Immunol 2003;111:1032–40.
Huang CD, Chen HH, Wang CH, et al. Human neutrophil-derived elastase induces airway smooth muscle cell proliferation. Life Sci 2004;74:2479–92.
Carroll N, Elliot J, Morton A, et al. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147:405–10.
Saetta M, Di Stefano A, Turato G, et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:822–6.
Lambert RK, Wiggs BR, Kuwano K, et al. Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 1993;74:2771–81.
Brightling CE, Ward R, Woltmann G, et al. Induced sputum inflammatory mediator concentrations in eosinophilic bronchitis and asthma. Am J Respir Crit Care Med 2000;162:878–82.
Birring SS, Parker D, Brightling CE, et al. Induced sputum inflammatory mediator concentrations in chronic cough. Am J Respir Crit Care Med 2004;169:15–9.
Gibson PG. Cough is an airway itch? Am J Respir Crit Care Med 2004;169:1–2.
Yosipovitch G, Greaves MW, Schmelz M. Itch. Lancet 2003;361:690–4.(C E Brightling and I D Pa)
Correspondence to:
Dr I D Pavord
Institute for Lung Health, Department of Respiratory Medicine, University Hospitals of Leicester, Groby Road, Leicester LE3 9QP, UK; ian.pavord@uhl-tr.nhs.uk
Role of inflammatory cell location in the pathogenesis of asthma, COPD, and cough
Keywords: inflammatory cells; microlocalisation; asthma; chronic obstructive pulmonary disease
Most inflammatory mediators are rapidly inactivated once they leave the cell so that they act across distances of only a few microns. It is therefore likely that microlocalisation between inflammatory and structural cells is a fundamental organising principle of airway inflammation and repair.
Enthusiasm for the view that microlocalisation is important in obstructive airway diseases has been fuelled by studies which showed inflammatory cells within the airway smooth muscle in asthma and chronic obstructive pulmonary disease (COPD) but not in normal controls. In asthma the airway smooth muscle is infiltrated by mast cells, predominantly of the chymase positive phenotype. Mast cell numbers correlate inversely with airway responsiveness,1 which suggests that interactions between mast cells and smooth muscle cells are central in the development of the disordered physiology in asthma. The strength of this assertion is underpinned by the paucity of mast cells within the airway smooth muscle in eosinophilic bronchitis, a condition that presents with chronic cough and shares many of the immunopathological features of asthma but is not associated with airflow obstruction or airway hyperresponsiveness.1–3 Importantly, there is evidence that mast cells infiltrating the airway smooth muscle bundle are activated; a necroscopic study of fatal and non-fatal asthma has shown that there is a marked increase in mast cell degranulation in the airway smooth muscle in both the large and small airways.4
A recent study has investigated whether a similar phenomenon occurs in COPD. Baraldo et al5 found increased numbers of neutrophils and CD8+ cells—but not mast cells—in the small airways of smokers with COPD, and the neutrophil number was inversely related to percentage predicted forced expiratory volume in 1 second (FEV1). This is consistent with an earlier study which showed that the number of neutrophils in the airway smooth muscle in smokers is related to air trapping as determined by CT scanning.6 However, in this study Berger et al found that the number of chymase positive mast cells was more closely related with air trapping. Most of the subjects in these studies had undergone lung resection for cancer so, although the airways studied were considered to be from unaffected areas, there remains the possibility that the underlying lung cancer contributed to the inflammatory changes. Nevertheless, the body of evidence strongly suggests that microlocalisation of inflammatory cells within the airway smooth muscle bundle is an important feature of obstructive airway diseases. This raises two key questions:
Why do specific inflammatory cells accumulate in the airway smooth muscle in asthma and COPD?
How do interactions between these inflammatory cells and airway smooth muscle cells lead to disordered airway function?
WHY DO SPECIFIC INFLAMMATORY CELLS ACCUMULATE IN THE AIRWAY SMOOTH MUSCLE IN ASTHMA AND COPD?
Selective recruitment of inflammatory cells to the airway smooth muscle is likely to be mediated by smooth muscle derived chemoattractants and by maintenance of the correct microenvironment to maintain cell differentiation and survival. Airway smooth muscle has a significant secretory capacity, so it clearly has the potential to recruit inflammatory cells.7 For example, CXCL8 (IL-8) and CXCL10 (IP-10) released by activated airway smooth muscle in COPD may mediate neutrophil and CD8+ cell migration into the airway smooth muscle bundle.8,9 A plethora of chemotactic factors for mast cells are released by airway smooth muscle—notably, stem cell factor (SCF),10 CCL11 (eotaxin),11 CXCL8 (IL-8),8 and transforming growth factor (TGF)-?.10 We have recently shown that CXCR3 is the most abundantly expressed chemokine receptor on human lung mast cells within airway smooth muscle, that human lung mast cell migration is induced by the CXCR3 ligand CXCL10, and that CXCL10 is released preferentially from asthmatic airway smooth muscle cells compared with those from healthy controls.12 Future studies investigating the effects of inhibiting this pathway will be of particular interest.
It is likely that a number of other chemokines play a role in the recruitment of inflammatory cells into the airway and it may be that the release of chemotaxins by airway smooth muscle varies in response to different stimuli such as cigarette smoke, infection, or allergen exposure. Future studies should explore the relative importance of these triggers and the associated chemotaxins that are released in promoting inflammatory cell infiltration into the airway smooth muscle. It is also important to investigate why some inflammatory cells, notably eosinophils, are rarely seen in the airway smooth muscle in spite of appropriate chemotactic signals.
HOW DO INTERACTIONS BETWEEN THESE INFLAMMATORY CELLS AND AIRWAY SMOOTH MUSCLE CELLS LEAD TO DISORDERED AIRWAY FUNCTION?
Activation of the inflammatory cells within the airway smooth muscle bundle would be predicted to have important consequences on airway smooth muscle function. Following mast cell degranulation the mediators histamine, PGD2 and LTC4 are released which are all potent agonists for airway smooth muscle contraction.13 Mast cell cytokines may further contribute to airway hyperreponsiveness. The mast cells in the airway smooth muscle bundles in asthma express IL-13,14 and IL-13 has been shown to attenuate relaxation to ? agonists and to augment contractility to acetylcholine.15,16 The effect of neutrophil derived mediators on airway smooth muscle function is less clear, with conflicting reports from animal studies showing that elastase can increase and diminish smooth muscle responsiveness.17,18
The interactions between inflammatory cells and airway smooth muscle cells may have more long term consequences. A number of mast cell mediators including histamine,19 tryptase,20 and LTD4,21 as well as the neutrophil product elastase,22 promote airway smooth muscle proliferation. Increased airway smooth muscle mass is a well established feature of both asthma23 and COPD.24 In asthma this occurs predominantly in the large airway and in COPD in the small airways. A study using a computational model of the effects of increased muscle mass has suggested that it is the most important abnormality responsible for the increased airflow resistance observed in response to bronchoconstricting stimuli in both asthma and COPD.25 The relative contribution of airway wall smooth muscle mass to overall airway wall thickness in the small airways is much greater than that in the large airways. Thus, increased smooth muscle mass in the small airways is likely to make a significant contribution to the development of fixed airflow obstruction characteristic of COPD and sometimes seen in persistent chronic severe asthma. The role of interactions between inflammatory cells and smooth muscle cells in the development of airway wall remodelling in asthma and COPD offers exciting opportunities for future research.
FUTURE STUDIES
The recognition of the importance of microlocalisation is not confined to inflammatory cells and airway smooth muscle cells but is probably equally critical in interactions with other structural cells such as the epithelium, fibroblasts, mucosal glands, and nerve cells. Eosinophilic bronchitis, cough variant asthma, and idiopathic chronic cough are associated with increased concentration of mast cell products in sputum,26,27 and we have suggested that localisation of mast cells to sensory nerve endings might be important in the development of cough reflex hypersensitivity and cough. A rather similar interaction is thought to be important in the genesis of itch.28,29 Understanding the fundamental steps that are involved in the migration of inflammatory cells towards structural cells such as the airway smooth muscle and the interactions between these cells may provide us with novel targets for the future treatment of asthma, COPD, and cough. Researchers interested in the immunopathology of airway diseases therefore need to be mindful of the importance of "location, location, location".
REFERENCES
Brightling CE, Bradding P, Symon FA, et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002;346:1699–705.
Brightling CE, Ward R, Goh KL, et al. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med 1999;160:406–10.
Brightling CE, Symon FA, Birring SS, et al. Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax 2003;58:528–32.
Carroll NG, Mutavdzic S, James AL. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur Respir J 2002;19:879–85.
Baraldo S, Turato G, Badin C, et al. Neutrophilic infiltration within the airway smooth muscle in patients with COPD. Thorax 2004;59:308–12.
Berger P, Laurent F, Begueret H, et al. Structure and function of small airways in smokers: relationship between air trapping at CT and airway inflammation. Radiology 2003;228:85–94.
Knox AJ, Pang L, Johnson S, et al. Airway smooth muscle function in asthma. Clin Exp Allergy 2000;30:606–14.
John M, Au BT, Jose PJ, et al. Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2 cytokines and corticosteroids. Am J Respir Cell Mol Biol 1998;18:84–90.
Hardaker EL, Bacon AM, Carlson KA, et al. Regulation of TNF-- and IFN--induced CXCL10 expression: participation of the airway smooth muscle in the pulmonary inflammatory response in chronic obstructive pulmonary disease. FASEB J 2004;18:191–3.
Berger P, Girodet O, Begueret H, et al. Tryptase-stimulated human airway smooth muscle cells induce cytokine synthesis and mast cell chemotaxis. FASEB J 2003;17:2139–41.
Hirst SJ, Hallsworth MP, Peng O, et al. Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1? and is mediated by the interleukin-4 receptor -chain. Am J Respir Crit Care Med 2002;165:1161–71.
Brightling CE, Ammitt AJ, Berger P, et al. CXCL10 (IP-10) is a novel mast cell chemokine and is released by asthmatic airway smooth muscle (abstract). Thorax 2003;58 (Suppl III):iii4–5.
Brightling CE, Bradding P, Pavord ID, et al. New insights into the role of the mast cell in asthma. Clin Exp Allergy 2003;33:550–6.
Brightling CE, Symon FA, Holgate ST, et al. Interleukin-4 and -13 expression is co-localized to mast cells within the airway smooth muscle in asthma. Clin Exp Allergy 2003;33:1711–6.
Grunstein MM, Hakonarson H, Leiter J, et al. IL-13 dependent autocrine signalling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2002;282:520–8.
Laporte JC, Moore PE, Baraldo S, et al. Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med 2001;164:141–8.
Gray PR, Mitchell HW. Intramural elastase injection increases responsiveness of isolated bronchial segments. Pulm Pharmacol 1996;9:239–43.
Christensen GC, Lev A, Ryan J, et al. Rabbit trachealis tension responses to receptor-mediated agonists are diminished by elastase. Am J Respir Cell Mol Biol 1992;6:498–503.
Panettieri RA Jr, Yadvish PA, Kelly AM, et al. Histamine stimulates proliferation of airway smooth muscle and induces c-Fos expression. Am J Physiol 1990;259:L365–71.
Berger P, Perng DW, Thabrew H, et al. Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle. J Appl Physiol 2001;91:1372–9.
Espinosa K, Bosse Y, Stankova J, et al. CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4. J Allergy Clin Immunol 2003;111:1032–40.
Huang CD, Chen HH, Wang CH, et al. Human neutrophil-derived elastase induces airway smooth muscle cell proliferation. Life Sci 2004;74:2479–92.
Carroll N, Elliot J, Morton A, et al. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147:405–10.
Saetta M, Di Stefano A, Turato G, et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:822–6.
Lambert RK, Wiggs BR, Kuwano K, et al. Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 1993;74:2771–81.
Brightling CE, Ward R, Woltmann G, et al. Induced sputum inflammatory mediator concentrations in eosinophilic bronchitis and asthma. Am J Respir Crit Care Med 2000;162:878–82.
Birring SS, Parker D, Brightling CE, et al. Induced sputum inflammatory mediator concentrations in chronic cough. Am J Respir Crit Care Med 2004;169:15–9.
Gibson PG. Cough is an airway itch? Am J Respir Crit Care Med 2004;169:1–2.
Yosipovitch G, Greaves MW, Schmelz M. Itch. Lancet 2003;361:690–4.(C E Brightling and I D Pa)