Inflammation in asthma: The cornerstone of the disease and target of therapy,☆☆,

https://doi.org/10.1016/S0091-6749(98)70002-8Get rights and content

Abstract

Asthma is a chronic disease associated with variable levels of airflow obstruction. Considerable evidence has been obtained to show that airway inflammation is a major factor in the pathogenesis of asthma in associated bronchial hyperresponsiveness, and in the level of disease severity. The inflammatory pattern in asthma is multicellular in nature, with mast cells, neutrophils, eosinophils, T lymphocytes, and epithelial cells participating in the response. Furthermore, it is known that mediators, cytokines, and chemokines from these cells contribute to the orchestration of the inflammatory process. Because airway inflammation appears to be a critical etiologic feature of asthma, it has become the target of therapy. In this review the features of airway inflammation will be examined, and the effect of therapeutic agents on markers of airway injury will be discussed. Establishing, understanding, and finally controlling the features of airway inflammation have given insight to disease pathogenesis and the effectiveness of various treatments. The integral role of inhaled corticosteroids in modifying the complex inflammatory component of asthma will be explored, with special focus on the high degree of efficacy associated with this treatment—vis-á-vis other therapeutic agents—in preventing or blocking specific proinflammatory markers. (J Allergy Clin Immunol 1998;102:S17-S22)

Section snippets

ACTIVATORS OF ASTHMA

Many factors influence the severity of asthma. Recently, activators of asthma have been divided into 2 general classes: inducers (causes) and provokers (exacerbations) (Fig 1).8

. Activators of asthma.

Inducers are factors that not only increase the intensity of asthma or its severity but also influence the level of underlying inflammation. As a consequence, inducers increase asthma severity, and these effects can persist long after initial exposure to a causative agent. More specifically,

MAST CELLS

Mast cells develop from bone marrow progenitor cells and are found in increased numbers in the airways of patients with asthma.14 These cells have unique characteristics, which include high-affinity receptors for IgE (Table I).

. Mast cells

Activation—IgE dependent
Mediators
 Spasmogens
 Inducers of inflammation:Proteases
Cytokines
Regulation by anti-inflammatory therapy
 Corticosteroids:↓ Growth and development
 Cromones:? Modification of mediator release
 Theophylline:Perhaps none
 Leukotriene modifiers:

EOSINOPHILS

Antigen inhalation causes eosinophil recruitment to the lung in asthma, and these cells are the principal effector cells in the resulting inflammatory process (Table II).

. Eosinophils

Principal effector cells in the inflammatory process
Mediators
 Cysteinyl leukotrienes
 Granular proteins
 Cytokines
Mechanisms of participation
Migration and upregulation
Effects are noted in the mucosa and epithelium
Regulation by anti-inflammatory therapy
 Corticosteroids:Induce apoptosis
Suppress lymphocyte generation of IL-5

LYMPHOCYTES

Activated lymphocytes are an important component of airway inflammation in asthma (Table III).

. Lymphocytes

Source of inflammatory mediators
 TH2 -like cytokine profile
Memory/long-lived cell
Regulation by anti-inflammatory therapy
 Corticosteroids:Inhibit cytokine production
 Cromones:Effect not established
 Theophylline:? Effect on lymphocyte subpopulations
 Leukotriene modifiers:Effect not established

T H2 , T helper cell 2.

Based on observations in mice, considerable interest has emerged that

EPITHELIAL CELLS

Epithelial cells are another source of proinflammatory mediators in asthma including eicosanoids, cytokines, chemokines, and nitric oxide (Table IV).72, 73

. Epithelial cells

Source of mediators
 Eicosanoids
 Cytokines
 Chemokines
 Nitric oxide
Regulation by anti-inflammatory therapy
 Corticosteroids:Inhibit transcription of cytokines (IL-8, TNF-α, RANTES, GM-CSF)
Inhibit inducible nitric oxide synthesis
  Cromones:Effect not established
  Theophylline:Effect not established
  Leukotriene modifiers:Effect not

SUMMARY

Airway inflammation is an important feature of asthma. The intensity of inflammation is influenced by various inducers and provokers of asthma. Furthermore treatment with anti-inflammatory medications modifies the pattern of inflammation in asthma and the generation or expression of proinflammatory mediators. Studies with anti-inflammatory medications have provided valuable insight into mechanisms of asthma and the actions of drugs used in the management of this disease. Although these

References (78)

  • P Diaz et al.

    Bronchoalveolar lavage in asthma: the effect of disodium cromoglycate (cromolyn) on leukocyte counts, immunoglobulins, and complement

    J Allergy Clin Immunol

    (1984)
  • P Sullivan et al.

    Anti-inflammatory effects of low-dose oral theophylline in atopic asthma

    Lancet

    (1994)
  • LA Laitinen et al.

    Leukotriene E4 and granulocytic infiltration into asthmatic airways

    Lancet

    (1993)
  • S Romagnani

    Induction of TH 1 and TH 2 responses: a key role for the “natural” immune response?

    Immunol Today

    (1992)
  • PJ Barnes et al.

    Nitric oxide and asthmatic inflammation

    Immunol Today

    (1995)
  • M Di Rosa et al.

    Glucocorticoids inhibit the induction of nitric oxide synthase in macrophages

    Biochem Biophys Res Commun

    (1990)
  • ST. Holgate

    Asthma: a dynamic disease of inflammation and repair

  • MS Dunnill et al.

    A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis, and in emphysema

    Thorax

    (1969)
  • MS. Dunnill

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

    J Clin Pathol

    (1960)
  • R Beasley et al.

    Cellular events in the bronchi in mild asthma and after bronchial provocation

    Am Rev Respir Dis

    (1989)
  • PK Jeffery et al.

    Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity

    Am Rev Respir Dis

    (1989)
  • J Bousquet et al.

    Eosinophilic inflammation in asthma

    N Engl J Med

    (1990)
  • JG Kirby et al.

    Bronchoalveolar cell profiles of asthmatic and nonasthmatic subjects

    Am Rev Respir Dis

    (1987)
  • National Asthma Education and Prevention Program. Expert Panel Report 2: guidelines for the diagnosis and management of asthma

    (April 1997)
  • PM O’Byrne et al.

    Late asthmatic responses

    Am Rev Respir Dis

    (1987)
  • JR Shaver et al.

    Kinetics of the development and recovery of the lung from IgE-mediated inflammation: dissociation of pulmonary eosinophilia, lung injury, and eosinophil-active cytokines

    Am J Respir Crit Care Med

    (1997)
  • JB Sedgwick et al.

    Immediate and late airway response of allergic rhinitis patients to segmental antigen challenge

    Am Rev Respir Dis

    (1991)
  • WR. Roche

    Fibroblasts and asthma

    Clin Exp Allergy

    (1991)
  • M Castells et al.

    Identification and immunotyping of committed non-granulated mast cell precursors in the peripheral blood of a patient with aggressive systemic mastocytosis

    FASEB J

    (1995)
  • SE Wenzel et al.

    Activation of pulmonary mast cells by bronchoalveolar allergen challenge: in vivo release of histamine and tryptase in atopic subjects with and without asthma

    Am Rev Respir Dis

    (1988)
  • R Aalbers et al.

    Bronchial lavage and bronchoalveolar lavage in allergen-induced single early and dual asthmatic responders

    Am Rev Respir Dis

    (1993)
  • 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)
  • P Bradding et al.

    Heterogeneity of human mast cells based on cytokine content

    J Immunol

    (1995)
  • R Djukanovic et al.

    Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma

    Am Rev Respir Dis

    (1992)
  • PK Jeffery et al.

    Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma: a quantitative light and electron microscopic study

    Am Rev Respir Dis

    (1992)
  • RP. Schleimer

    Effects of glucocorticoids on inflammatory cells relevant to their therapeutic applications in asthma

    Am Rev Respir Dis

    (1990)
  • RP Schleimer et al.

    Effects of dexamethasone on mediator release from human lung fragments and purified human lung mast cells

    J Clin Invest

    (1983)
  • VL Cohan et al.

    Dexamethasone does not inhibit the release of mediators from human mast cells residing in airway, intestine, or skin

    Am Rev Respir Dis

    (1989)
  • MK Church et al.

    The characteristics of inhibition of histamine release from human lung fragments by sodium cromoglycate, salbutamol, and chlorpromazine

    Br J Pharmacol

    (1983)
  • Cited by (113)

    • Pharmacological screening of Acalypha indica L.: Possible role in the treatment of asthma

      2022, Journal of Ethnopharmacology
      Citation Excerpt :

      Asthma is an inflammatory disease that comprises of many features, including airway hyperreactivity, bronchospasm, and inflammation of the airway. Among these features, airway inflammation is considered a primary feature that acts as a driving force for airway hyperreactivity and the tendency to bronchospasm (Busse, 1998). In addition, regulation of airway inflammation is governed through the bronchial epithelium via recruitment of various cell types, including eosinophils and T cells (Djukanovic, 2002).

    • Improving Management of Severe Asthma: BiPAP and Beyond

      2018, Clinical Pediatric Emergency Medicine
      Citation Excerpt :

      The treatments in most mild to moderate acute asthma exacerbations include inhaled oxygen therapy, systemic corticosteroids, inhaled β2-agonists such as albuterol, and ipratropium. Asthma is a disease of chronic inflammation, airway hyperresponsiveness, and airway obstruction.7,8 Corticosteroids facilitate asthma treatment by providing therapeutic synergy with β2-agonists to improve bronchodilatation by increasing β-receptors on the surface of bronchial smooth muscles.

    • Prophylactic effect of rosmarinic acid on tracheal responsiveness, white blood cell count and oxidative stress markers in lung lavage of sensitized rats

      2018, Pharmacological Reports
      Citation Excerpt :

      Also, oxidative stress aggravates airway inflammation in bronchial asthma, by inducing diverse pro-inflammatory mediators, enhancing airway hyper-responsiveness, increasing mucus secretion and inducing bronchospasm [26]. Additionally, increased oxidant markers (NO and MDA) and decreased antioxidant factors (thiol groups, SOD and CAT) in asthma have been reported previously [9,27]. TR to methacholine and OVA, percentages of eosinophils, monocytes, and neutrophils and the levels of oxidant biomarkers in BALF, were significantly decreased but lymphocytes and antioxidant biomarkers were significantly increased in groups treated with dexamethasone and two higher concentrations of RA compared to untreated S animals.

    • Cell-penetrating peptides can confer biological function: Regulation of inflammatory cytokines in human monocytes by MK2 inhibitor peptides

      2011, Journal of Controlled Release
      Citation Excerpt :

      The inflammatory response is essential for human health and the maintenance of homeostasis; however, chronic inflammation contributes to the pathogenesis of many disease states and results in the destruction of tissue. Inflammation and the production of proinflammatory cytokines play a role in the perpetuation of many diseases including inflammatory bowel disease [3], asthma [4], rheumatoid arthritis [5,6], atherosclerosis [7], and cancer [8]. The propagation of inflammation occurs as a result of the activated resident cells and invading immune cells at the site of inflammation.

    View all citing articles on Scopus

    From the Department of Medicine, University of Wisconsin–Madison.

    ☆☆

    Reprint requests: William W. Busse, MD, University of Wisconsin–Madison, Department of Medicine, J5/220 Clinical Science Center, 600 Highland Ave, Madison, WI 53792-2454.

    0091-6749/98/$5.00 + 0  1/0/93575

    View full text