Is the neutrophil the key effector cell in severe asthma?
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《胸》
1 Department of Respiratory Medicine, Norfolk and Norwich University Hospital, Norwich, UK
2 Institute of Lung Health, Glenfield Hospital, Leicester, UK
3 Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK
Correspondence to:
Professor E R Chilvers
Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK; erc24@cam.ac.uk
The importance of the neutrophil as the dominant inflammatory cell in many of the non-atopic and more severe phenotypes of asthma is now clear
Keywords: asthma; neutrophil; inflammation
Eosinophilic inflammation has long been considered one of the most distinctive pathological hallmarks of asthma1 and features in many contemporary definitions of this disease. A plethora of studies published from the mid 1990s onwards have suggested, however, that airway eosinophilia is not a universal finding. This has fuelled debate that discrete pathological phenotypes of asthma may exist, with the neutrophil—rather than the eosinophil—dominating in certain circumstances.2–4 We present data that support the current renewed interest in the neutrophil as a primary driver of airways inflammation, particularly in the most severe forms of asthma. There are also some intriguing data to suggest that, when the eosinophil has been "red carded" and disappears from the inflamed airway, the neutrophil may be drawn in and act as the substitute granulocyte.
The hypothesis that the eosinophil is the key effector cell involved in the pathogenesis of asthma has run into trouble for several reasons: (1) eosinophilic inflammation is present in the airway lumen of only 50% of asthmatic subjects;4 (2) even intense eosinophilic inflammation, as occurs in eosinophilic bronchitis, fails to induce asthma;5 (3) many asthma exacerbations occur in the absence of airway eosinophilia; (4) specific anti-eosinophil strategies—for example, anti-IL-5 and IL-12—are poorly efficacious in vivo;6–8 and (5) eosinophilic deficient mice have now been engineered and this modification has little impact on the airway pathology induced in response to ovalbumin sensitisation.9
A strong association has now been established between neutrophilic inflammation of the airways and severe asthma,10–12 corticosteroid resistant asthma,13–15 asthma exacerbations,2 nocturnal asthma,16 "asthma in smokers",17 occupational asthma,18 and "sudden onset" fatal asthma.19 It is noteworthy that, in the study by Little and colleagues12 conducted in a group of 59 asthmatics, forced expiratory volume in 1 second (FEV1) was inversely proportional to neutrophil numbers. These studies analysed neutrophil numbers in all airway compartments including the small airways and, where measured, neutrophil numbers correlated well with markers of neutrophil degranulation which implies that these cells are also activated.10,12,15,20–22 These findings are of particular importance given the disproportionate health costs associated with treating patients with severe disease.23
These data set up a number of critical questions—namely:
What are the principal drivers of neutrophil influx into asthmatic airways?
Can any of the existing asthma treatments be implicated in airway neutrophilia?
How do we quantify neutrophil trafficking in this disease?
What are the most promising therapeutic options to inhibit this process?
It is now widely argued that certain physical triggers including viruses, lipopolysaccharides, and ozone may be more important inducers of airway neutrophilia than any primary immunological cause,21,24 and epithelial derived IL-8 again stands out as one of the most likely chemoattractants for neutrophils.25 While in severe disease eosinophils and neutrophils are usually found together,13 cross sectional studies suggest that neutrophils may gradually replace eosinophils in proportion to the severity and/or duration of the disease.10 This view is supported by the study of Hauber and co-workers26 who took bronchial wall and transbronchial biopsy specimens from a group of 12 asthmatics before and after treatment with HFA-flunisolide. They found a dramatic fall in the number of IL-5 and eotaxin mRNA positive cells and eosinophils in both the central and peripheral airways and a corresponding and equally marked rise in the number of neutrophils at these sites. A similar effect has been reported elsewhere27,28 and may reflect the widely cited capacity of corticosteroids to induce eosinophil apoptosis and phagocytic removal and yet inhibit the same process in neutrophils.29–31 The possibility that the airway neutrophilia develops as a primary pathological response and hence represents a distinct inflammatory phenotype is supported by studies which show that this subgroup of patients is non-atopic and has an impaired response to inhaled corticosteroids.14,15
One intriguing insight into the potential high state of flux of neutrophils in the airway wall is provided by the study of Martin et al16 who performed bronchial lavage in patients with nocturnal asthma and found a greater than threefold increase in the number of granulocytes in bronchoalveolar lavage (BAL) fluid samples at 04.00 hours compared with 16.00 hours. This suggests a high rate of turnover of these cells and implies that neutrophils may have a surprisingly short half life (<8 hours) in asthmatic airways. The plasticity of the airway neutrophilia is further supported by experimental data obtained using an equine model of asthma where complete resolution of the neutrophilic airway response occurred over a matter of a few days following removal of the mouldy hay challenge.32 In this model the alveolar macrophages appeared to make a significant contribution to the clearance of apoptotic neutrophil corpses from within the airway lumen. Thus, if neutrophils do not reside within the asthmatic airways for protracted periods due to the presence of efficient natural clearance mechanisms, strategies designed to block influx—which presumably occurs at the post capillary venule level within the bronchial circulation—may be highly efficacious. Recent studies have revealed the pivotal role of the enzyme phosphoinositide 3-kinase in controlling neutrophil migration, activation and survival,33,34 and the discovery of neutrophil specific isoforms makes selective therapeutic targeting with conventional small molecular weight inhibitors a realistic prospect. Certainly, the introduction of a p85 phosphoinositide 3-kinase construct delivered using an HIV-TAT based protein delivery system in mice has a dramatic protective effect on ovalbumin induced airways inflammation.35
Thus, while the role of the eosinophil in mediating airways inflammation in mild and moderate atopic asthma appears secure,36,37 the importance of the neutrophil as perhaps the dominant inflammatory cell in many of the non-atopic and more severe phenotypes of asthma is now equally clear. Corticosteroids are highly effective in promoting the resolution of eosinophilic inflammation but far less so in neutrophilic inflammation and, indeed, may even facilitate the arrival and survival of these cells in the airway wall.
FOOTNOTES
The work in the authors’ laboratories is supported by the Wellcome Trust, British Heart Foundation, Asthma UK, MRC, Papworth Hospital and the British Lung Foundation.
REFERENCES
Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990;323:1033–9.
Fahy JV, Kim KW, Liu J, et al. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995;95:843–52.
Turner MO, Hussack P, Sears MR, et al. Exacerbations of asthma without sputum eosinophilia. Thorax 1995;50:1057–61.
Douwes J, Gibson P, Pekkanen J, et al. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002;57:643–8.
Brightling CE, Symon FA, Birring SS, et al. Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax 2003;58:528–32.
Leckie MJ, Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000;356:2144–8.
Bryan SA, O’Connor BJ, Matti S, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000;356:2149–53.
Kips JC, O’Connor BJ, Langley SJ, et al. Effect of SCH55700, a humanised anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med 2003;167:1655–9.
Humbles AA, Lloyd CM, McMillan SJ, et al. A critical role for eosinophils in allergic airways remodeling. Science 2004;305:1776–9.
Wenzel SE, Szefler SJ, Leung DYM, et al. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997;156:737–43.
Jatakanon A, Uasuf C, Maziak W, et al. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999;160:1532–9.
Little SA, Macleod KJ, Chalmers GW, et al. Association of forced expiratory volume with disease duration and sputum neutrophils in chronic asthma. Am J Med 2002;112:446–52.
Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999;160:1001–8.
Pavord ID, Brightling CE, Woltmann G, et al. Non-eosinophilic corticosteroid unresponsive asthma. Lancet 1999;353:2213–4.
Green RH, Brightling CE, Woltmann G, et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002;57:875–9.
Martin RJ, Cicutto LC, Smith HR, et al. Airways inflammation in nocturnal asthma. Am Rev Respir Dis 1991;143:351–7.
Chalmers GW, Macleod KJ, Thomson L, et al. Smoking and airway inflammation in patients with mild asthma. Chest 2001;120:1917–22.
Anees W, Huggins V, Pavord ID, et al. Occupational asthma due to low molecular weight agents: eosionphilic and non-eosinophilic variants. Thorax 2002;57:231–6.
Sur S, Crotty TB, Kephart GM, et al. Sudden-onset fatal asthma: a distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis 1993;148:713–9.
Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001;119:1329–36.
Stenfors N, Pourazar J, Blomberg A, et al. Effect of ozone on bronchial mucosal inflammation in asthmatic and healthy subjects. Respir Med 2002;96:352–8.
Lacoste JY, Bousquet J, Chanez P, et al. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease. J Allergy Clin Immunol 1993;92:537–48.
Serra-Batlles J, Plaza V, Morejon E, et al. Costs of asthma according to the degree of severity. Eur Respir J 1998;12:1322–6.
Wark PAB, Johnston SL, Moric I, et al. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur Respir J 2002;19:68–75.
Ordonez CL, Shaughnessy TE, Matthay MA, et al. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: clinical and biological significance. Am J Respir Crit Care Med 2000;161:1185–90.
Hauber HP, Gotfried M, Newman K, et al. Effect of HFA-flunisolide on peripheral lung inflammation in asthma. J Allergy Clin Immunol 2003;112:58–63.
Tanizaki Y, Kitani H, Mifune T, et al. Effects of glucocorticoids on humoral and cellular immunity and on airway inflammation in patients with steroid-dependent intractable asthma. J Asthma 1993;30:485–92.
Nguyen LT, Lim S, Oates T, et al. Increase in airway neutrophils after oral but not inhaled corticosteroid therapy in mild asthma. Respir Med 2005;99:200–7.
Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes. J Immunol 1995;154:4719–25.
Meagher LC, Cousin JM, Seckl JR, et al. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosionophilic granulocytes. J Immunol 1996;156:4422–8.
Liu Y, Cousin JM, Hughes J, et al. Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes. J Immunol 1999;162:3639–46.
Brazil TJ, Dagleish MP, McGorum BC, et al. Kinetics of pulmonary neutrophil recruitment and clearance in a natural and spontaneously resolving model of airway inflammation. Clin Exp Allergy 2005; (in press).
Cadwallader KA, Condliffe AM, McGregor A, et al. Regulation of phosphoinositide 3-kinase activity and PtdIns(3,4,5)P3 accumulation by neutrophil priming agents. J Immunol 2002;169:3336–44.
Cowburn AS, Cadwallader K, Reed B, et al. Role of PI3-kinase dependent BAD phosphorylation and altered transcription in cytokine-mediated neutrophil survival. Blood 2002;100:2607–16.
Myou S, Leff AR, Myo S, et al. Blockade of inflammation and airway hyperresponsiveness in immune-sensitized mice by dominant-negative phosphoinositide 3-kinase-TAT. J Exp Med 2003;198:1573–82.
Aalbers R, Kauffman HF, Vrugt B, et al. Allergen-induced recruitment of inflammatory cells in lavage 3 and 24 h after challenge in allergic asthmatic lungs. Chest 1993;103:1178–84.
Gauvreau GM, Watson RM, O’Byrne PM. Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am J Respir Crit Care Med 1999;160:640–7.(A V Kamath1, I D Pavord2,)
2 Institute of Lung Health, Glenfield Hospital, Leicester, UK
3 Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK
Correspondence to:
Professor E R Chilvers
Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK; erc24@cam.ac.uk
The importance of the neutrophil as the dominant inflammatory cell in many of the non-atopic and more severe phenotypes of asthma is now clear
Keywords: asthma; neutrophil; inflammation
Eosinophilic inflammation has long been considered one of the most distinctive pathological hallmarks of asthma1 and features in many contemporary definitions of this disease. A plethora of studies published from the mid 1990s onwards have suggested, however, that airway eosinophilia is not a universal finding. This has fuelled debate that discrete pathological phenotypes of asthma may exist, with the neutrophil—rather than the eosinophil—dominating in certain circumstances.2–4 We present data that support the current renewed interest in the neutrophil as a primary driver of airways inflammation, particularly in the most severe forms of asthma. There are also some intriguing data to suggest that, when the eosinophil has been "red carded" and disappears from the inflamed airway, the neutrophil may be drawn in and act as the substitute granulocyte.
The hypothesis that the eosinophil is the key effector cell involved in the pathogenesis of asthma has run into trouble for several reasons: (1) eosinophilic inflammation is present in the airway lumen of only 50% of asthmatic subjects;4 (2) even intense eosinophilic inflammation, as occurs in eosinophilic bronchitis, fails to induce asthma;5 (3) many asthma exacerbations occur in the absence of airway eosinophilia; (4) specific anti-eosinophil strategies—for example, anti-IL-5 and IL-12—are poorly efficacious in vivo;6–8 and (5) eosinophilic deficient mice have now been engineered and this modification has little impact on the airway pathology induced in response to ovalbumin sensitisation.9
A strong association has now been established between neutrophilic inflammation of the airways and severe asthma,10–12 corticosteroid resistant asthma,13–15 asthma exacerbations,2 nocturnal asthma,16 "asthma in smokers",17 occupational asthma,18 and "sudden onset" fatal asthma.19 It is noteworthy that, in the study by Little and colleagues12 conducted in a group of 59 asthmatics, forced expiratory volume in 1 second (FEV1) was inversely proportional to neutrophil numbers. These studies analysed neutrophil numbers in all airway compartments including the small airways and, where measured, neutrophil numbers correlated well with markers of neutrophil degranulation which implies that these cells are also activated.10,12,15,20–22 These findings are of particular importance given the disproportionate health costs associated with treating patients with severe disease.23
These data set up a number of critical questions—namely:
What are the principal drivers of neutrophil influx into asthmatic airways?
Can any of the existing asthma treatments be implicated in airway neutrophilia?
How do we quantify neutrophil trafficking in this disease?
What are the most promising therapeutic options to inhibit this process?
It is now widely argued that certain physical triggers including viruses, lipopolysaccharides, and ozone may be more important inducers of airway neutrophilia than any primary immunological cause,21,24 and epithelial derived IL-8 again stands out as one of the most likely chemoattractants for neutrophils.25 While in severe disease eosinophils and neutrophils are usually found together,13 cross sectional studies suggest that neutrophils may gradually replace eosinophils in proportion to the severity and/or duration of the disease.10 This view is supported by the study of Hauber and co-workers26 who took bronchial wall and transbronchial biopsy specimens from a group of 12 asthmatics before and after treatment with HFA-flunisolide. They found a dramatic fall in the number of IL-5 and eotaxin mRNA positive cells and eosinophils in both the central and peripheral airways and a corresponding and equally marked rise in the number of neutrophils at these sites. A similar effect has been reported elsewhere27,28 and may reflect the widely cited capacity of corticosteroids to induce eosinophil apoptosis and phagocytic removal and yet inhibit the same process in neutrophils.29–31 The possibility that the airway neutrophilia develops as a primary pathological response and hence represents a distinct inflammatory phenotype is supported by studies which show that this subgroup of patients is non-atopic and has an impaired response to inhaled corticosteroids.14,15
One intriguing insight into the potential high state of flux of neutrophils in the airway wall is provided by the study of Martin et al16 who performed bronchial lavage in patients with nocturnal asthma and found a greater than threefold increase in the number of granulocytes in bronchoalveolar lavage (BAL) fluid samples at 04.00 hours compared with 16.00 hours. This suggests a high rate of turnover of these cells and implies that neutrophils may have a surprisingly short half life (<8 hours) in asthmatic airways. The plasticity of the airway neutrophilia is further supported by experimental data obtained using an equine model of asthma where complete resolution of the neutrophilic airway response occurred over a matter of a few days following removal of the mouldy hay challenge.32 In this model the alveolar macrophages appeared to make a significant contribution to the clearance of apoptotic neutrophil corpses from within the airway lumen. Thus, if neutrophils do not reside within the asthmatic airways for protracted periods due to the presence of efficient natural clearance mechanisms, strategies designed to block influx—which presumably occurs at the post capillary venule level within the bronchial circulation—may be highly efficacious. Recent studies have revealed the pivotal role of the enzyme phosphoinositide 3-kinase in controlling neutrophil migration, activation and survival,33,34 and the discovery of neutrophil specific isoforms makes selective therapeutic targeting with conventional small molecular weight inhibitors a realistic prospect. Certainly, the introduction of a p85 phosphoinositide 3-kinase construct delivered using an HIV-TAT based protein delivery system in mice has a dramatic protective effect on ovalbumin induced airways inflammation.35
Thus, while the role of the eosinophil in mediating airways inflammation in mild and moderate atopic asthma appears secure,36,37 the importance of the neutrophil as perhaps the dominant inflammatory cell in many of the non-atopic and more severe phenotypes of asthma is now equally clear. Corticosteroids are highly effective in promoting the resolution of eosinophilic inflammation but far less so in neutrophilic inflammation and, indeed, may even facilitate the arrival and survival of these cells in the airway wall.
FOOTNOTES
The work in the authors’ laboratories is supported by the Wellcome Trust, British Heart Foundation, Asthma UK, MRC, Papworth Hospital and the British Lung Foundation.
REFERENCES
Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990;323:1033–9.
Fahy JV, Kim KW, Liu J, et al. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995;95:843–52.
Turner MO, Hussack P, Sears MR, et al. Exacerbations of asthma without sputum eosinophilia. Thorax 1995;50:1057–61.
Douwes J, Gibson P, Pekkanen J, et al. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002;57:643–8.
Brightling CE, Symon FA, Birring SS, et al. Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax 2003;58:528–32.
Leckie MJ, Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000;356:2144–8.
Bryan SA, O’Connor BJ, Matti S, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000;356:2149–53.
Kips JC, O’Connor BJ, Langley SJ, et al. Effect of SCH55700, a humanised anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med 2003;167:1655–9.
Humbles AA, Lloyd CM, McMillan SJ, et al. A critical role for eosinophils in allergic airways remodeling. Science 2004;305:1776–9.
Wenzel SE, Szefler SJ, Leung DYM, et al. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997;156:737–43.
Jatakanon A, Uasuf C, Maziak W, et al. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999;160:1532–9.
Little SA, Macleod KJ, Chalmers GW, et al. Association of forced expiratory volume with disease duration and sputum neutrophils in chronic asthma. Am J Med 2002;112:446–52.
Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999;160:1001–8.
Pavord ID, Brightling CE, Woltmann G, et al. Non-eosinophilic corticosteroid unresponsive asthma. Lancet 1999;353:2213–4.
Green RH, Brightling CE, Woltmann G, et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002;57:875–9.
Martin RJ, Cicutto LC, Smith HR, et al. Airways inflammation in nocturnal asthma. Am Rev Respir Dis 1991;143:351–7.
Chalmers GW, Macleod KJ, Thomson L, et al. Smoking and airway inflammation in patients with mild asthma. Chest 2001;120:1917–22.
Anees W, Huggins V, Pavord ID, et al. Occupational asthma due to low molecular weight agents: eosionphilic and non-eosinophilic variants. Thorax 2002;57:231–6.
Sur S, Crotty TB, Kephart GM, et al. Sudden-onset fatal asthma: a distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am Rev Respir Dis 1993;148:713–9.
Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001;119:1329–36.
Stenfors N, Pourazar J, Blomberg A, et al. Effect of ozone on bronchial mucosal inflammation in asthmatic and healthy subjects. Respir Med 2002;96:352–8.
Lacoste JY, Bousquet J, Chanez P, et al. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease. J Allergy Clin Immunol 1993;92:537–48.
Serra-Batlles J, Plaza V, Morejon E, et al. Costs of asthma according to the degree of severity. Eur Respir J 1998;12:1322–6.
Wark PAB, Johnston SL, Moric I, et al. Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. Eur Respir J 2002;19:68–75.
Ordonez CL, Shaughnessy TE, Matthay MA, et al. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: clinical and biological significance. Am J Respir Crit Care Med 2000;161:1185–90.
Hauber HP, Gotfried M, Newman K, et al. Effect of HFA-flunisolide on peripheral lung inflammation in asthma. J Allergy Clin Immunol 2003;112:58–63.
Tanizaki Y, Kitani H, Mifune T, et al. Effects of glucocorticoids on humoral and cellular immunity and on airway inflammation in patients with steroid-dependent intractable asthma. J Asthma 1993;30:485–92.
Nguyen LT, Lim S, Oates T, et al. Increase in airway neutrophils after oral but not inhaled corticosteroid therapy in mild asthma. Respir Med 2005;99:200–7.
Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes. J Immunol 1995;154:4719–25.
Meagher LC, Cousin JM, Seckl JR, et al. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosionophilic granulocytes. J Immunol 1996;156:4422–8.
Liu Y, Cousin JM, Hughes J, et al. Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes. J Immunol 1999;162:3639–46.
Brazil TJ, Dagleish MP, McGorum BC, et al. Kinetics of pulmonary neutrophil recruitment and clearance in a natural and spontaneously resolving model of airway inflammation. Clin Exp Allergy 2005; (in press).
Cadwallader KA, Condliffe AM, McGregor A, et al. Regulation of phosphoinositide 3-kinase activity and PtdIns(3,4,5)P3 accumulation by neutrophil priming agents. J Immunol 2002;169:3336–44.
Cowburn AS, Cadwallader K, Reed B, et al. Role of PI3-kinase dependent BAD phosphorylation and altered transcription in cytokine-mediated neutrophil survival. Blood 2002;100:2607–16.
Myou S, Leff AR, Myo S, et al. Blockade of inflammation and airway hyperresponsiveness in immune-sensitized mice by dominant-negative phosphoinositide 3-kinase-TAT. J Exp Med 2003;198:1573–82.
Aalbers R, Kauffman HF, Vrugt B, et al. Allergen-induced recruitment of inflammatory cells in lavage 3 and 24 h after challenge in allergic asthmatic lungs. Chest 1993;103:1178–84.
Gauvreau GM, Watson RM, O’Byrne PM. Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation. Am J Respir Crit Care Med 1999;160:640–7.(A V Kamath1, I D Pavord2,)