Inflammatory cells in asthma: Mechanisms and implications for therapy

doi:10.1067/mai.2003.22

Journal of Allergy and Clinical Immunology

Volume 111, Issue 1, Supplement, January 2003, Pages S5-S17

https://doi.org/10.1067/mai.2003.22 Get rights and content

Abstract

Recent clinical studies have brought asthma's complex inflammatory processes into clearer focus, and understanding them can help to delineate therapeutic implications. Asthma is a chronic airway inflammatory disease characterized by the infiltration of airway T cells, CD⁺ (T helper) cells, mast cells, basophils, macrophages, and eosinophils. The cysteinyl leukotrienes also are important mediators in asthma and modulators of cytokine function, and they have been implicated in the pathophysiology of asthma through multiple mechanisms. Although the role of eosinophils in asthma and their contribution to bronchial hyperresponsiveness are still debated, it is widely accepted that their numbers and activation status are increased. Eosinophils may be targets for various pharmacologic activities of leukotriene receptor antagonists through their ability to downregulate a number of events that may be key to the effector function of these cells. (J Allergy Clin Immunol 2003;111:S5–17.)

Section snippets

Inflammatory cells in asthma

Asthma is a chronic airway inflammatory disease characterized by infiltration of the airway T cells. In both normal and asthmatic airway mucosa, the prominent cells are the T lymphocytes, which are activated in response to antigen stimulation, or during acute asthma exacerbations, and produce high levels of cytokines. They are subdivided into two broad subsets according to their surface cell markers and distinct functions: the CD4⁺ (T helper) and the CD8⁺ (T cytotoxic) cells. CD4⁺ cells are

Cytokines

The initial indication for cytokine involvement in the pathogenesis of asthma came from studies performed in the early 1990s showing that atopic asthma was associated with local T_H2 cytokine expression. IL-3, IL-4, IL-5, and GM-CSF were upregulated in asthmatic patients relative to control subjects. These cytokines were significantly upregulated after antigen challenge, and their receptors were identified locally on the surface of inflammatory cells.⁶ Studies have confirmed the existence of the

Leukotrienes

Although not cytokines, the CysLTs have emerged as important mediators in asthma and as modulators of cytokine function. Leukotrienes are lipid mediators resulting from the catabolism of the arachidonic acid (AA) released from the cell membrane by phospholipase A₂ after cell activation. After its release, AA is metabolized either by the cyclooxygenase pathway, generating prostaglandins and thromboxanes, or by the 5-lipoxy-genase (5-LO) pathway, which in association with 5-LO-activating protein

Mast cells

Mast cells make up a small proportion of cells recovered by BAL, but within the airway tissue as many as 20% of inflammatory cells are mast cells.34, 35 In BAL specimens, normal mast cell numbers range from 0.02% to 0.48%.36, 37 Normal mast cell numbers36, 38, 39, 40, 41 or increases of 2- to 6-fold, have been reported in patients with atopic34, 37, 42, 43, 44, 45, 46, 47 as well as nonatopic asthma.⁴⁸ On the airway surface and in the submucosa, mast cells are mostly the mucosal type,

Basophils

Basophils possess high levels of the FcϵRI receptor and are capable of an immediate response to allergen. Although basophils are not present in healthy airways, they are present in the airways of asthmatic persons under a variety of circumstances. Basophils have been reported in the sputum of patients with symptomatic asthma,⁶² and recent studies have demonstrated basophil infiltration of airways in cases of fatal asthma63, 64 and in bronchial biopsy specimens from patients with asthma.65, 66

Macrophages

Macrophages are the predominant cell recovered by BAL in both nonasthmatic and asthmatic persons. Although most macrophages are recovered from alveoli, small volume lavage or lavage of isolated airway segments⁷² supports macrophage predominance in conducting airways as well as alveoli. Thus, macrophages are well positioned to respond to and regulate inflammation along the airway. Although the prominence of macrophages along the airway surface and their diverse functions strongly implicate

Anti-IgE

In the pathogenesis of allergic disease, IgE plays a central role. Mast cells and basophils are the primary cells that bear the high-affinity IgE receptor, and a critical role for these cells is supported by the effect of anti-IgE therapy on the airway response to allergen bronchoprovocation. Omalizumab is a humanized murine monoclonal antibody (rhuMAb-E25) that binds to the same portion of IgE as the high-affinity IgE receptor. Because the anti-IgE antibody and the cell surface receptor

SAC

The cellular, mediator, and cytokine responses underlying the physiologic response to allergen exposure have been examined with the SAC model, in which allergen is instilled directly into an airway segment during bronchoscopy and events occurring within minutes, hours, or days can be examined, generally by BAL. This model also has been used to examine the effects of prednisone and leukotriene modifier therapy on inflammatory changes. Cellular effects of these asthma medications on BAL cells

Eosinophils

Activated T cells and eosinophils are important pathophysiologic elements in asthma (Fig 4).

. A scheme of putative immune and inflammatory events associated with the pathophysiology of asthma, with emphasis on early- versus late-phase asthmatic responses. Sites of potential anti-inflammatory action of LTRAs are shown by large arrows. ECP , Eosinophil cationic protein; EPO , eosinophil peroxidase; PG , prostaglandin; PAF , platelet activating factor; APC , antigen presenting cell; TCR , T-cell

Cyslts

Eosinophils are a rich source of CysLTs¹⁰³ that are derived from native AA by the action of phospholipase A₂.¹⁰⁷ Human eosinophils synthesize and release relatively large concentrations of LTC₄ (as much as 70 ng/10⁶ cells) after stimulation with the calcium ionophore A23187.¹⁰⁸ In general, eosinophils obtained from asthmatic subjects appear to produce more LTC₄ than do those from healthy control donors.109, 110 Experimentally, coculture of eosinophils with endothelial cells¹¹¹ or exogenous

Leukotriene modifiers

The contribution of the CysLTs in bronchoconstriction has been inferred from recent developments in the field of leukotriene-modifying therapies.33, 119, 120 LTD₄ receptor antagonists (montelukast, zafirlukast, and pranlukast) inhibit the biologic activities of LTD₄ and the other members of the CysLT family by competing for their receptors on smooth muscle cells.¹²¹ Clinical trials of LTRAs, including montelukast and zafirlukast,122, 123, 124, 125, 126 have significantly controlled asthma

Conclusions

The sensitized reaction to an allergen includes responses from T cells, mast cells, basophils, macrophages, and eosinophils. In the case of asthma and allergic rhinitis, the mediators released from these cells perpetuate the asthmatic inflammatory response, and the CysLTs have emerged as one of the important mediators.

In human beings, the 5-LO pathway is expressed only in myeloid cells, including mast cells, basophils, neutrophils, eosinophils, and alveolar macrophages. Eosinophils from

Questions and discussion

Marc Peters-Golden: Qutayba, is the epithelium capable of differentiating into mesenchymal-like cells, as they appear to do in the kidney? Could the smooth muscle cells that appear to be pushing up into the epithelial layer actually be the basal epithelial cells that are differentiating into smooth muscle cells instead?

Qutayba Hamid: We did not see any evidence that epithelial cells go to something that is not a cytocuritin-positive cell or what would probably look like a smooth muscle.

References (141)

J Chen et al.
CD4(+), CD25(+) T cells as regulators of alloimmune responses
Transplant Proc
(2001)
JE de Vries
The role of IL-13 and its receptor in allergy and inflammatory responses
J Allergy Clin Immunol
(1998)
J Louahed et al.
Interleukin 9 promotes influx and local maturation of eosinophils
Blood
(2001)
A Shimbara et al.
IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma
J Allergy Clin Immunol
(2000)
S Molet et al.
IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines
J Allergy Clin Immunol
(2001)
E Minshall et al.
IL-11 expression is increased in severe asthma: association with epithelial cells and eosinophils
J Allergy Clin Immunol
(2000)
SS Salvi et al.
The anti-inflammatory effects of leukotriene-modifying drugs and their use in asthma
Chest
(2001)
S Lam et al.
Release of leukotrienes in patients with bronchial asthma
J Allergy Clin Immunol
(1988)
K Shindo et al.
Plasma levels of leukotriene E₄ during clinical course of bronchial asthma and the effect of oral prednisolone
Chest
(1994)
DW Hay et al.
Cysteinyl leukotrienes in asthma: old mediators up to new tricks
Trends Pharmacol Sci
(1995)

AN Fonteh et al.

A decrease in remodeling accounts for the accumulation of arachidonic acid in murine mast cells undergoing apoptosis

J Biol Chem

(2001)

A Foresi et al.

Inflammatory markers in bronchoalveolar lavage and in bronchial biopsy in asthma during remission

Chest

(1990)

DH Broide et al.

Evidence of ongoing mast cell and eosinophil degranulation in symptomatic asthma airway

J Allergy Clin Immunol

(1991)

S Mattoli et al.

Cellular and biochemical characteristics of bronchoalveolar lavage fluid in symptomatic nonallergic asthma

J Allergy Clin Immunol

(1991)

SE Wenzel et al.

Bronchoalveolar lavage fluid mediator levels 5 minutes after allergen challenge in atopic subjects with asthma: relationship to the development of late asthmatic responses

J Allergy Clin Immunol

(1991)

BB Zehr et al.

Use of segmental airway lavage to obtain relevant mediators from the lungs of asthmatic and control subjects

Chest

(1989)

T Van Vyve et al.

Protein content in bronchoalveolar lavage fluid of patients with asthma and control subjects

J Allergy Clin Immunol

(1995)

JR Gordon et al.

Mast cells as a source of multifunctional cytokines

Immunol Today

(1990)

AJ Macfarlane et al.

Basophils, eosinophils, and mast cells in atopic and nonatopic asthma and in late-phase allergic reactions in the lung and skin

J Allergy Clin Immunol

(2000)

WL Eschenbacher et al.

A technique for isolated airway segment lavage

Chest

(1987)

AB Tonnel et al.

Stimulation of alveolar macrophages in asthmatic patients after local provocation test

Lancet

(1983)

JA Rankin

The contribution of alveolar macrophages to hyperreactive airway disease

J Allergy Clin Immunol

(1989)

RW Fuller

The role of the alveolar macrophage in asthma

Respir Med

(1989)

J MacDermot et al.

Synthesis of leukotriene B₄, and prostanoids by human alveolar macrophages: analysis by gas chromatography/mass spectrometry

Prostaglandins

(1984)

GC Kane et al.

A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings

J Allergy Clin Immunol

(1996)

MC Liu et al.

Effects of prednisone on the cellular responses and release of cytokines and mediators after segmental allergen challenge of asthmatic subjects

J Allergy Clin Immunol

(2001)

LA Laitinen et al.

Leukotriene E₄ and granulocytic infiltration into asthmatic airways

Lancet

(1993)

M Asano et al.

Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation

J Exp Med

(1996)

H Turner et al.

Signalling through the high-affinity IgE receptor Fc epsilonRI

Nature

(1999)

A Suto et al.

Role of CD4(+) CD25(+) regulatory T cells in T helper 2 cell-mediated allergic inflammation in the airways

Am J Respir Crit Care Med

(2001)

AM Thornton et al.

CD4⁺CD25⁺ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production

J Exp Med

(1998)

KF Chung et al.

Cytokines in asthma

Thorax

(1999)

J Louahed et al.

Interleukin-9 upregulates mucus expression in the airways

Am J Respir Cell Mol Biol

(2000)

O Einarsson et al.

Interleukin-11 in respiratory inflammation

Ann N Y Acad Sci

(1995)

SE Wenzel et al.

Elevated levels of leukotriene C₄ in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge

Am Rev Respir Dis

(1990)

Y Kikawa et al.

Exercise-induced urinary excretion of leukotriene E₄ in children with atopic asthma

Pediatr Res

(1991)

PS Creticos et al.

Peptide leukotriene release after antigen challenge in patients sensitive to ragweed

N Engl J Med

(1984)

SJ Chu et al.

In situ amplification of 5-lipoxygenase and 5-lipoxygenase-activating protein in allergic airway inflammation and inhibition by leukotriene blockade

J Immunol

(2000)

AS Cowburn et al.

Overexpression of leukotriene C₄ synthase in bronchial biopsies from patients with aspirin-intolerant asthma

J Clin Invest

(1998)

AP Sampson et al.

Profound overexpression of leukotriene C₄ synthase in bronchial biopsies from aspirin-intolerant asthmatic patients

Int Arch Allergy Immunol

(1997)

SM Nasser et al.

Inflammatory cell populations in bronchial biopsies from aspirin- sensitive asthmatic subjects

Am J Respir Crit Care Med

(1996)

JM Drazen et al.

Leukotrienes and airway responses

Am Rev Respir Dis

(1987)

GL Piacentini et al.

The potential roles of leukotrienes in bronchial asthma

Am Rev Respir Dis

(1991)

WR Henderson

The role of leukotrienes in inflammation

Ann Intern Med

(1994)

A Wanner et al.

Mucociliary clearance in the airways

Am J Respir Crit Care Med

(1996)

T Ahmed et al.

Abnormal mucociliary transport in allergic patients with antigen-induced bronchospasm: role of slow reacting substance of anaphylaxis

Am Rev Respir Dis

(1981)

DC Underwood et al.

Persistent airway eosinophilia after leukotriene (LT) D₄ administration in the guinea pig: modulation by the LTD₄ receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody

Am J Respir Crit Care Med

(1996)

SP O'Hickey et al.

Leukotrienes C₄, D₄, and E₄ enhance histamine responsiveness in asthmatic airways

Am Rev Respir Dis

(1991)

M Kurosawa et al.

Inhibition by a novel peptide leukotriene receptor antagonist ONO-1078 of airway wall thickening and airway hyperresponsiveness to histamine induced by leukotriene C4 or leukotriene D₄ in guinea-pigs

Clin Exp Allergy

(1994)

MS Dunhill

The pathology of asthma, with special reference to changes in the bronchial mucosa

J Clin Pathol

(1960)

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^☆: Reprint requests: Qutayba Hamid, MD, PhD, Professor of Medicine, Meakins-Christie Laboratories, McGill University, 3626 St-Urbain St, Montreal, Quebec, Canada H2X 2P2.

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Inflammatory cells in asthma: Mechanisms and implications for therapy☆

Abstract

Section snippets

Inflammatory cells in asthma

Cytokines

Leukotrienes

Mast cells

Basophils

Macrophages

Anti-IgE

SAC

Eosinophils

Cyslts

Leukotriene modifiers

Conclusions

Questions and discussion

Transplant Proc

J Allergy Clin Immunol

Blood

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

Chest

Trends Pharmacol Sci

J Biol Chem

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

Immunol Today

J Allergy Clin Immunol

Chest

Lancet

J Allergy Clin Immunol

Respir Med

Prostaglandins

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation

J Exp Med

Signalling through the high-affinity IgE receptor Fc epsilonRI

Nature

Role of CD4(+) CD25(+) regulatory T cells in T helper 2 cell-mediated allergic inflammation in the airways

Am J Respir Crit Care Med

CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production

J Exp Med

Cytokines in asthma

Thorax

Interleukin-9 upregulates mucus expression in the airways

Am J Respir Cell Mol Biol

Interleukin-11 in respiratory inflammation

Ann N Y Acad Sci

Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge

Am Rev Respir Dis

Exercise-induced urinary excretion of leukotriene E4 in children with atopic asthma

Pediatr Res

Peptide leukotriene release after antigen challenge in patients sensitive to ragweed

N Engl J Med

In situ amplification of 5-lipoxygenase and 5-lipoxygenase-activating protein in allergic airway inflammation and inhibition by leukotriene blockade

J Immunol

Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma

J Clin Invest

Profound overexpression of leukotriene C4 synthase in bronchial biopsies from aspirin-intolerant asthmatic patients

Int Arch Allergy Immunol

Inflammatory cell populations in bronchial biopsies from aspirin- sensitive asthmatic subjects

Am J Respir Crit Care Med

Leukotrienes and airway responses

Am Rev Respir Dis

The potential roles of leukotrienes in bronchial asthma

Am Rev Respir Dis

The role of leukotrienes in inflammation

Ann Intern Med

Mucociliary clearance in the airways

Am J Respir Crit Care Med

Abnormal mucociliary transport in allergic patients with antigen-induced bronchospasm: role of slow reacting substance of anaphylaxis

CD4⁺CD25⁺ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production

Elevated levels of leukotriene C₄ in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge

Exercise-induced urinary excretion of leukotriene E₄ in children with atopic asthma

Overexpression of leukotriene C₄ synthase in bronchial biopsies from patients with aspirin-intolerant asthma

Profound overexpression of leukotriene C₄ synthase in bronchial biopsies from aspirin-intolerant asthmatic patients

Persistent airway eosinophilia after leukotriene (LT) D₄ administration in the guinea pig: modulation by the LTD₄ receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody

Leukotrienes C₄, D₄, and E₄ enhance histamine responsiveness in asthmatic airways

Inhibition by a novel peptide leukotriene receptor antagonist ONO-1078 of airway wall thickening and airway hyperresponsiveness to histamine induced by leukotriene C4 or leukotriene D₄ in guinea-pigs