Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU
Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children (JACI, 2011). Approximately 9% of the U.S. population has asthma - 9% of adult asthmatics have aspirin-exacerbated respiratory disease (AERD) (http://goo.gl/FIeE9).
Pathogenesis of Inflammation in Asthma
Inflammation in asthma (mind map). Inflammometry: the current state of play in asthma - FeNO and more. Thorax, 2012.
Lymphocytes
CD4, Th2 helper lymphocytes are the central effector cells in airway inflammation. They secrete a variety of cytokines which promote eosinophils, mucous secretion, production of IgE and adhesion molecules such as VCAM-1.
CD4, Th2
Central effector cells
Cytokine release
T cell predominance in lung diseases:
CD8: hypersensitivity pneumonitis (HP) and COPD
Th2, CD4: Asthma, ABPA, pulmonary eosinophilia
Th1, CD4: granulomatous TB, sarcoid, berylliosis
Lower Airway Changes in Asthma and COPD
Cellular infiltrate: CD4 in asthma vs. CD8 in COPD.
Th1 and Th2 subsets (mind map)
Overview of adhesion molecules, 3 groups remembered by the mnemonic SIS:
Selectins
Integrins
Superfamily Ig
Mast cells
Mast cells release preformed (histamine and tryptase) and newly generated mediators (leukotrienes, prostaglandins, cytokines) which cause mucosal inflammation.
Mast cells. Image source: Wikipedia.
Mast cells are subdivided into 2 types based on proteinase content:
TC mast cells -- Tryptase and Chymase in granules
T mast cells -- Tryptase only granules
Mast cells
Mediator release
Mucosal inflammation
Mast cells (mind map).
Macrophages
Macrophages represent 90% of cells recovered by bronchoalveolar lavage (BAL) in normal persons and in stable asthmatic patients.
Eosinophils
Eosinophils were found to be associated with asthma more than 30 years ago. In patients with asthma, there is an an inverse relationship between lung function and the number of circulating eosinophils, eosinophilis in the bronchoalveolar lavage fluid and lung tissue.
Eosinophil. Image source: Wikipedia.
Mediators from eosinophils are remembered by the mnemonic CML EEE:
Cytokines
MBP
Lipid Mediators
EDN
ECP
EPO
A diagram of eosinophil mediators
Eosinophils
Emit
Eight mediators (at least 8, the first C in the mnemonic covers cytokines, chemokines and growth factors)
Receptors for IgE
High-Affinity IgE Receptor (FcεRI)
The high affinity receptor for IgE (FcεRI) is expressed on mast cells (fixed in tissues) and basophils (circulating in blood). The level of FcεRI expression is regulated by levels of IgE. FcεRI molecule consists of 4 chains: alpha, beta and 2 gamma.
Low-Affinity IgE Receptor (FcεRII)
The role of FcεRII is not clear. Variations in the low-affinity IgE receptor gene (FCER2 or II) are associated with an increase in severe exacerbations in children with asthma. There are several reasons that a patient may not respond to inhaled corticosteroid therapy in asthma and genetics, including FCER2 variants, may be an important one.
Mutations
- Germline mutations occur in germ cells and can be inherited via the reproductive cells.
- Somatic mutations involve cells outside the reproductive system and generally do not get inheride in the subsequent generations.
- Single nucleotide polymorphisms (SNPs) are variations in DNA that occurs when a single nucleotide in a gene of an individual is different from that of other individuals. SNPs occur at a higher frequency than mutations.
Variations in some of the SNPs were associated with increased IgE levels and increased risk of severe exacerbations of asthma during inhaled corticosteroid treatment. Therefore, FCER2 variations may lead to asthma exacerbations despite inhaled steroids. Personalized medicine via pharmacogenetics can lead to genetic studies guiding therapeutic decisions in the future.
Neutrophils
Neutrophils contribute to inflammatory injury but their exact role still remains obscure. Increased number of neutrophils are present in the airways during the late-phase reaction after allergen challenge, in fatal or nocturnal asthma, and in severe asthma.
Leukocyte migration
The migration of leukocytes from blood vessels into airways is regulated by different adhesion molecules such as:
- leukocyte function-associated antigen-1 (LFA-1)
- macrophage antigen-1 (MAC-1)
- ICAM-1 and 2, VCAM-1
- VLA
Overview of adhesion molecules, 3 groups remembered by the mnemonic SIS:
Selectins
Integrins
Superfamily Ig
Rhinoviruses upregulate both ICAM-1 and VCAM-1 which, in turn, can enhance leukocyte migration into the airways.
Nuclear Transcription Factor NF-κB
Nuclear factor-κB (NF-κB, kappa B) is a transcription regulator for genes which produce inflammatory mediators. NF-κB could be a molecular target for development of new asthma therapy.
Mechanism of NF-κB action. While in an inactivated state, NF-κB is located in the cytosol complexed with the inhibitory protein IκBα. In the process of activation, IκBα dissociates from NF-κB. The activated NF-κB moves to the nucleus where it binds to specific sequences of DNA. Image source: Wikipedia.
Bronchial Epithelium
The epithelium plays a dual role in asthma -- it is the target of inflammatory mediators, and the same time, a source of pro-inflammatory mediators.
Oxidative stress
Inflammatory mediators lead to production of oxygen radicals which damage different airway components. One of such radicals is nitric oxide (NO). It is synthesized from L-arginine by the enzyme nitric oxide synthase (NOS). Measuring exhaled nitric oxide (FeNO) can serve as a marker of airway inflammation because levels increase in asthma exacerbation and decrease with corticosteroid therapy.
Nitric oxide or nitrogen monoxide has the chemical formula NO. Image source: Wikipedia.
Active and passive smoking decreased FeNO levels in adults.
Leukotrienes
Eicosanoids are signaling molecules made by oxygenation of 20-carbon essential fatty acids. There are 4 families of eicosanoids (PP-LT): prostaglandins (PG), prostacyclins (PGI), leukotrienes (LT) and thromboxanes (TX). Leukotrienes are one of the key inflammatory mediators in asthma. They are produced via an ezymatic cascade from the phospholipid bilayer of the cell membrane.
Eicosanoid synthesis. Image source: Wikipedia.
Mast cells quickly generate different eicosanoids mediators from the metabolism of arachidonic acid: leukotrienes and prostglandins (LTC4, LTB4, PGD2). These substances are produced within minutes of IgE-receptor crosslinking on the surface of mast cells.
Mast cell mediators
Airway remodeling
Airway remodeling consists of:
- bronchial smooth muscle thickening
- irreversible narrowing of the airways
Airway remodeling is present in many patients with long-standing asthma history. In general, asthmatics have an accelerated rate of airway function decline compared to healthy controls (38 mL/year vs. 22 mL/year). This is largely due to airway remodeling.
Viruses
Rhinoviruses upregulate both ICAM-1 and VCAM-1 which in turn enhances leukocyte migration into the airways. This may explain why patients with asthma are more prone to exacerbations when they catch the common cold. Both rhinovirus and respiratory syncytial virus (RSV) upregulate pro-inflammatory cytokines such as IL-6, IL-8 and GM-CSF.
Molecular surface of a rhinovirus, showing protein spikes. Image source: Wikipedia.
Intercellular adhesion molecule 1 (CD54), human rhinovirus receptor. Image source: Wikipedia.
Leukotrienes
Eicosanoids are signaling molecules made by oxygenation of 20-carbon essential fatty acids. There are 4 families of eicosanoids (PP-LT): prostaglandins (PG), prostacyclins (PGI), leukotrienes (LT) and thromboxanes (TX). Leukotrienes are one of the key inflammatory mediators in asthma. They are produced via an ezymatic cascade from the phospholipid bilayer of the cell membrane.
Eicosanoid synthesis. Image source: Wikipedia.
Mast cells quickly generate different eicosanoids mediators from the metabolism of arachidonic acid: leukotrienes and prostglandins (LTC4, LTB4, PGD2). These substances are produced within minutes of IgE-receptor crosslinking on the surface of mast cells.
Mast cell mediators
Airway remodeling
Airway remodeling consists of:
- bronchial smooth muscle thickening
- irreversible narrowing of the airways
Airway remodeling is present in many patients with long-standing asthma history. In general, asthmatics have an accelerated rate of airway function decline compared to healthy controls (38 mL/year vs. 22 mL/year). This is largely due to airway remodeling.
Viruses
Rhinoviruses upregulate both ICAM-1 and VCAM-1 which in turn enhances leukocyte migration into the airways. This may explain why patients with asthma are more prone to exacerbations when they catch the common cold. Both rhinovirus and respiratory syncytial virus (RSV) upregulate pro-inflammatory cytokines such as IL-6, IL-8 and GM-CSF.
Molecular surface of a rhinovirus, showing protein spikes. Image source: Wikipedia.
Intercellular adhesion molecule 1 (CD54), human rhinovirus receptor. Image source: Wikipedia.
Allergic sensitization is associated with rhinovirus-, but not other virus-, induced wheezing in children. http://goo.gl/PghX
Electron micrograph of RSV. Image source: Wikipedia.
Nervous System
The cholinergic nervous system maintains resting bronchial tone and stimulates mucus secretion. In some patients, bronchospasm seems to be predominant to inflammatory component.
Mucus secretion
Currently, there is no effective therapy for airway hypersecretion
- Creola bodies - clusters of surface epithelial cells
- Charcot-Leyden crystals - a pair of hexagonal pyramids joined at their bases. Normally colorless, they are stained purplish-red by trichrome. They consist of lysophospholipase
Environmental pollutants and the immune system
Exposure to tobacco smoke and other air pollutants induces allergic inflammation in the lung. The basic pro-inflammatory effect could be similar to one observed in pathogenesis of CAD and CVA in patients exposed to tobacco smoke and particulate matter pollutants. Indoor particulate matter increases asthma morbidity in children with non-atopic and atopic asthma (http://goo.gl/H4Kv2).
The hygiene hypothesis
Decreased atopic sensitization associated with living in a farm was explored by studying bacteria found in cowsheds. Acinetobacter lwoffii and Lactococcus lactis shifted the immune response toward the secretion of TH1 cytokines in a murine model. One begins to wonder if biotherapy with bacterial extracts would be in the future of studies of allergy prevention.
References
Allergy and Immunology MKSAP, 3rd edition.
A/I Images: Neutrophils in asthma. What is their role? Allergy Notes, 05/2007.
Exhaled nitric oxide (FeNO) in asthma and sinusitis. Allergy Notes, 09/2007.
Why children with asthma get sick in September? Allergy Notes, 08/2007.
Variations in Receptor Gene Contribute to Asthma Exacerbations. Medscape, 01/2008; J Allergy Clin Immunol 2007;120:1285-1291.
Advances in basic and clinical immunology in 2007. Journal of Allergy and Clinical Immunology - Volume 122, Issue 1 (July 2008).
Related reading
Electron micrograph of RSV. Image source: Wikipedia.
Nervous System
The cholinergic nervous system maintains resting bronchial tone and stimulates mucus secretion. In some patients, bronchospasm seems to be predominant to inflammatory component.
Mucus secretion
Currently, there is no effective therapy for airway hypersecretion
Sputum findings in asthma
- Curschmann’s spirals - corkscrew-shaped twists of condensed mucus
- Creola bodies - clusters of surface epithelial cells
- Charcot-Leyden crystals - a pair of hexagonal pyramids joined at their bases. Normally colorless, they are stained purplish-red by trichrome. They consist of lysophospholipase
Environmental pollutants and the immune system
Exposure to tobacco smoke and other air pollutants induces allergic inflammation in the lung. The basic pro-inflammatory effect could be similar to one observed in pathogenesis of CAD and CVA in patients exposed to tobacco smoke and particulate matter pollutants. Indoor particulate matter increases asthma morbidity in children with non-atopic and atopic asthma (http://goo.gl/H4Kv2).
The hygiene hypothesis
Decreased atopic sensitization associated with living in a farm was explored by studying bacteria found in cowsheds. Acinetobacter lwoffii and Lactococcus lactis shifted the immune response toward the secretion of TH1 cytokines in a murine model. One begins to wonder if biotherapy with bacterial extracts would be in the future of studies of allergy prevention.
What is the most potent bronchoconstrictor?
(A) LTB4
(B) LTC4
(C) acetylcholine
(D) histamine
(E) thromboxane A2 (TXA2)
(F) methacholine
Answer: B
CysLTs are the most potent bronchoconstrictor agents yet discovered, about 100-1000 times more potent than histamine. The second most potent bronchoconstrictor is thromboxane A2 (TXA2).
Cysteinyl‐LTs and LTB4 are, respectively, the most potent bronchoconstrictor agents and one of the most effective leukocyte chemotaxins yet.
References
Allergy and Immunology MKSAP, 3rd edition.
A/I Images: Neutrophils in asthma. What is their role? Allergy Notes, 05/2007.
Exhaled nitric oxide (FeNO) in asthma and sinusitis. Allergy Notes, 09/2007.
Why children with asthma get sick in September? Allergy Notes, 08/2007.
Variations in Receptor Gene Contribute to Asthma Exacerbations. Medscape, 01/2008; J Allergy Clin Immunol 2007;120:1285-1291.
Advances in basic and clinical immunology in 2007. Journal of Allergy and Clinical Immunology - Volume 122, Issue 1 (July 2008).
Recent Advances in the Pathophysiology of Asthma. Chest, June 2010 vol. 137 no. 6 1417-1426 (abstract).
Related reading
SNPwatch: Breathe Easier…New Insights From Asthma Research. 23andMe blog, 2010. http://goo.gl/ulJe
Published: 12/16/2007
Updated: 04/05/2012
Published: 12/16/2007
Updated: 04/05/2012
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