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Asthma and Its Pathophysiology

Dr. Deshinta Putri Mulya M.Sc, SpPD

Outline
Respiratory Tract Anatomy of the airways Airways Epithelium Physiology of the airways Asthma Pathophysiology Bronchoconstriction Bronchoinflamation

Airways epithelium
The major function of the respiratory epithelium was once thought to be a physical barrier. However, it constitutes the interface between the internal milieu and the external environment, secreting large number of immune system mediator, as well as being a primary target for inhaled respiratory drugs. Thus , the epithelium is in a unique position to translate geneenvironment interaction.
Knight DA, Holgate ST, The airway epithelium : Structural and functional properties in health disease Respirology. 2003 Dec;8(4):432-46

Epithelium
Ciiated Pseudostratified Columnar Epithelium : a) Cilliated Cells speciallized in cilliary modifications b) Goblet Cells secrete mucus which helps maintain epithelial moisture and traps particulate material and pathogens c) Basal Cells (cuboidal cells) may differentiate into other cells types within the epithelium.

The airway epithelial cell in Asthma


Creola bodies : shedding of columnar cells seen as a clumps in sputum Separation of columnar cells from basal attachment as the extent of epithelial damage due to bronchial hyperresponsiveness Increase in expression of heat shock protein, activation of transcription factor, elaborate number of inflammation modulating cytokines and chemokines Increase in the number of subepithelial myofibroblast that deposit interstitial collagens thickening and increased density of subepithelial basement membrane.

Holgate, S. T., D. E. Davies, P. M. Lackie, S. J. Wilson, S. M. Puddicombe, and J. L. Lordan. 2000. Epithelial-mesenchymal interactions in the pathogenesis of asthma. J. Allergy Clin. Immunol. 105:193204)

Holgate, S. T., D. E. Davies, P. M. Lackie, S. J. Wilson, S. M. Puddicombe, and J. L. Lordan. 2000. Epithelial-mesenchymal interactions in the pathogenesis of asthma. J. Allergy Clin. Immunol. 105:193204)

Creola bodies : shedding of columnar cells seen as a clumps i Increase in the number of subepithelial myofibroblast that deposit interstitial collagens thickening and increased density of subepithelial basement membrane.

Epithelial Injury
Exposure Agent : Viruses, Inhaled pollutants, allergen

Direct Response : Cytotoxicity or proteolysis

Indirect Respose : Involving immune and Inflamatory (Eosinophils and mast cells)

Alter cell function through induction of a stress response vial receptor mediated processes.

Distrupting intercellular adhesion, damaging tight junction, increasing paracellular permeability, initiating cell death,

Histologic sections of intrapulmonary bronchi demonstrating the altered structure and inflammation of the airway wall; hematoxylin-eosin (original magnification: 180). (A) A normal subject without a history of asthma who died accidentally, showing an intact surface pseudostratified ciliated columnar epithelium. The underlying reticular basement membrane is indistinct, there are few inflammatory cells, and small amounts of bronchial smooth muscle. (B) By contrast, in fatal asthma there is sloughing of the surface epithelium, a prominent homogeneous thickened reticular basement membrane of hyaline appearance, an intense infiltration of the mucosa by inflammatory cells, and enlargement of bronchial smooth muscle.

Lung Capacity

Spirograms and flow volume curves. (A) Restrictive ventilatory defect. (B) Normal spirogram. (C) Obstructive ventilatory defect. Reprinted with permission from Gold WM. Pulmonary function testing. In: Murray JF, Nadel JA, eds. Textbook of respiratory medicine. 3d ed. Philadelphia: Saunders, 2000:805.

RESPIRATORY PROCESS
In the absence of respiratory effort, the lung will come to lie at the point of the FRC. To move from this position and generate respiratory movement, two aspects need to be considered which oppose lung expansion and airflow and therefore need to be overcome by respiratory muscle activity. These are the airway resistance and the compliance of the lung and chest wall.

Resistance
The obstruction to airflow provided by the conducting airways, resulting largely from the larger airways, plus a contribution from tissue resistance resulting produced by friction as tissues of the lung slide over each other during respiration. An increase in resistance resulting from airway narrowing such as bronchospasm leads to obstructive airways disease

Complience
Denotes distensibility (stretchiness) and in clinical setting refers to the lung and chest wall combine. When compliance is low, the lung are stiffer and more effort is required to inflate the alveoli

Resistance & Compliance

Outline
Respiratory Tract Anatomy of the airways Airways Epithelium Physiology of the airways Asthma Pathophysiology Bronchoconstriction Bronchial Inflamation

Asthma is an airway disease that can be classified physiologically as a variable and partially reversible obstruction to air flow, and pathologically with overdeveloped mucus glands, airway thickening due to scarring and inflammation, and bronchoconstriction, the narrowing of the airways in the lungs due to the tightening of surrounding smooth muscle. Bronchial inflammation also causes narrowing due to edema and swelling caused by an immune response to allergens

A transverse slice of occluded bronchi (B) with adjacent arteries (A) in a subject who died after an asthma attack. A mixture of inflammatory exudate, mucus, bronchoconstriction, and thickening of the airway wall have contributed to the suffocation of this asthmatic.

Bronchoconstriction
The normal caliber of the bronchus is maintained by a balanced functioning of these nervous system, which operate reflexively. In the lungs, the sympathetic nervous system stimulates the respiratory passages to relax and open up, whereas the parasympathetic nervous system causes tightening and narrowing of the airways

Beta Blockage Theory


In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma. (Szentivanyi,
Andor (1968). "The Beta Adrenergic Theory of the Atopic Abnormality in Asthma". J.Allergy 42: 203

In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors. (Szentivanyi A., Ali K., Calderon EG., Brooks SM., Coffey RG., Lockey RF.
(1993). "The in vitro effect of Imunnoglobulin E {IgE} on cyclic AMP concentrations in A549 human pulmonary epithelial cells with or without beta adrenergic stimulation". J. Allergy Clin Immunol. 91: 379 )

Neurotransmitter
Excitatory Cholinergic e-NANC Inhibitory Noradrenergic i-NANC(Nitric Oxide)

(Goyal, Jaseja & Verma : Med Hypotheses. 2010 Apr;74(4):661-4)

Receptor
Subject with asthma had a significantly lower density of beta receptor compared to normal subject Patients with asthma may have lower isoproterenol cAMP response
(Sato T, Bewtra AK, Hopp RJ, Nair N, Townley RG, 1990 Alpha and beta adrenergic receptorsystem in bronchial asthma and in subjects without asthma : reduced mononuclear cell beta receptors in bronchial asthma J Allergy Clin Immunol Dec; 86 (6 Pt 1): 839 50)

In Conclusions

Clinical consequences of airway remodeling in asthma

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