Flashcards in Feb 6 - Asthma Deck (48):
What is asthma?
A chronic inflammatory disorder of the airways.
It involves mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils and epithelial cells
What are the symptoms of asthma?
Wheezing (noisy breathing), breathlessness, chest tightness, and coughing
When do symptoms typically arise?
Symptoms often at night or in early morning
What does inflammation lead to?
Inflammation can lead to airway hyper-responsiveness to various stimuli and airway obstruction, which can both lead to clinical symptoms
Which portion of the population is affected the most by asthma?
What are predictors of adult asthma persistence?
Diagnosis during school age, presence of atopy (genetic tendency to develop allergic diseases) and bronchial hyper-reactivity (BHR)
What is atopy?
A hereditary disorder marked by the tendency to develop to develop immediate allergic reactions to substances such as pollen, food, dander, and insect venoms and manifested by hay fever, asthma or similar allergic conditions
What is BHR?
BHR is a state of chronic hyper-reactive airways (bronchospasm), can be assessed with bronchiole challenge with methacoline or histamine (which can trigger bronchospasm is normal individuals but exaggerated in those with BHR)
What are non-modifiable risk factors?
Genetics (accounts for 60-80% of susceptibility)
Gender (male gender in childhood; female gender in adulthood)
What are modifiable risk factors?
Lower socioeconomic status
Exposure to second-hand smoke in utero and/or at a young age
Respiratory syncytial virus (RSV) exposure is a major cause of respiratory illness in young children
Reduced exposure to childhood infectious agents (aka the "hygiene hypothesis")
Does smoking cause asthma?
No (although it can cause COPD)
What is the hygiene hypothesis?
There is an imbalance between the allergic immune system and part of immune system which fights infections. Some studies showing lower risk of asthma in children exposed to high levels of bacteria (farms, daycare, few antibiotics)
Explain the imbalance between the allergic immune system and the immune system
Genetically susceptible individuals develop allergies and asthma by allowing the allergic immunologic system (T helper cell type 2 lymphocytes) to develop instead of the defensive immunologic system used to fight infections (T helper cell type 1 lymphocytes)
What are factors that can trigger asthma symptoms?
Respiratory tract infections (RSV, rhinovirus, influenza, mycoplasma pneumoniae)
Allergens (pollens, house dust mites, animal dander, fungal spores)
Environment (cold air, fog, smoke, pollution)
Food additives (sulphites, MSG)
Exercise (especially cold, dry climate)
Drugs/preservatives (ASA, NSAIDs, sulfites, benzalkonium chloride, some beta-blockers)
Occupational (Bakers (flour dust), farmers (hay mold), chemicals)
Emotions (Anxiety, stress, laughter)
Why does asthma make it hard to breathe?
In an asthmatic person, the muscles of the bronchial tubes tighten and thicken, and the air passages become inflamed and mucous-filled, making it difficult for air to move
What makes up the respiratory system?
Gas-exchanging organ (the lungs) and a "pump" that ventilates the lungs (the chest wall, the respiratory muscles)
What are eosinophils?
White blood cells of the immune system
What are goblet cells?
An epithelial cell that secretes mucous
What are neutrophils?
Type of white blood cell involved in inflammation and phagocytosis
What are hallmarks of asthma pathology?
Bronchial hyper-responsiveness (BHR)
Airway inflammation (chronic and acute)
Some degree of airflow obstruction (secondary to bronchial muscle spasm, mucous and/or oedema)
What is FEV1? Why is it important?
Forced vital capacity. It's the amount of air a person con forcefully expel in the first second of expiration. A healthy person can blow out 70-80% of their breath in the first second
What is sensitization?
Exposure of allergen mobilizes the production of specific IgE antibodies against that allergen. These IgE antibodies bind to receptors on mast cells
Describe the early phase of acute airway inflammation?
Re-exposure to the same allergen, promotes that specific IgE antibody that is stuck on the mast cell to bind to the allergen to form a cross linked complex. This triggers the mast cell to explode, liberating the release of pro-inflammatory mediators (histamine, reactive O2, etc.). This causes the contraction of muscle, mucous release, vasodilation, which leads to a restricted airway
Describe the late phase of acute airway inflammation
Occurs 3-10 hours post-exposure that can last up to 24 hours. Recruitment of more immune system mediators of inflammation (eosinophils, CD4+ helper cells, basophils, neutrophils, etc.). T cell activation results in B cell activation which develop into plasma cells that produce more IgE antibodies. It involves immune cells known as eosinphils (white blood cells). This causes mucous production, oedema/thickening of mucous, inflammation and swelling of the airways
Describe chronic airway inflammation?
Results from repeated exposure to the allergen
Can cause permanent damage to the lungs
Net result: permanent inflammation of the respiratory system even though symptoms are episodic
What is the first step of airway inflammation
The trigger (exposure to he allergen, irritant, cold air, exercise; this is an IgE dependant mechanism or indirectly via other processes) and release of inflammatory mediators (e.g., histamines, leukotrienes and prostaglandins) from bronchial mast cells, alveolar macrophages, T lymphocytes and epithelial cells
What is the second step of airway inflammation
These acute-acting mediators rapidly induce smooth muscle contraction, mucous hypersecretion and vasodilation with endothelial leakage and local oedema formation. Some mediators directly cause acute bronchoconstriction, termed "early-phase asthmatic response"
What is the third step of airway inflammation
Some of these preformed and rapidly acting mediators possess chemotactic activity, recruiting additional inflammatory cells such as eosinophils and neutrophils to airway mucosa, which cause injury. This so-called "late phase asthmatic response" series of events leading to continued airway inflammation and hyperresponsiveness results in epithelial damage, airway oedema, mucous hypersecretion and hyperresponsiveness of the bronchial smooth muscle
Describe the "late asthmatic response"
It is associated with an influx of inflammatory cells (eosinophils) into the bronchial mucosa and with an increase in bronchial reactivity that may last for several weeks after a single inhalation of allergen - more inflammation. The mediators responsible for this late response are thought to be cytokines characteristically produced by TH2 lymphocytes, especially interleukins 5, 9 and 13.
What do the cytokines in the late asthmatic response do?
These cytokines are thought to attract and activate eosinophils, stimulate IgE production by B lymphocytes, and stimulates mucous production by bronchial epithelial cells. It is not clear whether lymphocytes or mast cells in the airway mucosa are the primary source of the mediators responsible for the late inflammatory response, but the benefits of corticosteroid therapy are attributed to their inhibition of the production of pro-inflammatory cytokines i the airways
What do mast cells do?
Found throughout walls of respiratory tract
They are increased in number in patients with allergic asthma. Allergens bind to cell-bound IgE then mast cells release bronchoconstrictors (histamine, leukotrienes, prostaglandin D2, platelet activating factor) and eosinophil and neutrophil chemotactic factors (attract more mast cells to the area to make it worse
What do eosinophils do?
Activated eosinophils release inflammatory mediators such as leukotrienes and granule proteins to injure airway tissue
What do T-lymphocytes do?
Release cytokines (interleukins 4, 5, 9 and 13) that mediate allergic inflammation
Increased Th2 activity (reduced inhibitory Th1 cells) - possible Th1/Th2 imbalance (recall the hygiene hypothesis)
What do macrophages do?
In the normal airway they are scavengers which engulf and digest bacteria and other foreign materials
They are found in the large and small airways
They release inflammatory mediators such as platelet activating factor (PAF), leukotrienes (LT)
They release neutrophil chemotactic factor and eosinophil chemotactic factor which amplifies the inflammatory process
What do epithelial cells do?
Can be activated by IgE dependant mechanisms, viruses, pollutants, histamine
Normally they participate in mucocilliary clearance and removal of noxious agents, but in chronic asthma, epithelial shedding occurs, leading to heightened airway responsiveness, decreased clearance of noxious agents and a reduction in degrading enzymes that destroy pro-inflammatory neuropeptides
Name different mediators of inflammation
Arachadonic acid (AA) metabolized by cyclooxygenase (COX) to form prostaglandins/thromboxanes
Platelet activating factor (PAF)
Describe the role of histamine
Released by lung mast cells (allergens, exercise)
Induces smooth muscle constriction and bronchospasm
May play a role in mucosal oedema and mucous secretion
Describe the role of prostaglandins and thromboxanes
Prostaglandin D2 and F2alpha are bronchoconstrictors
Prostacyclin (PGI2) is a vasodilator causing inflammation and oedema
Thromboxane A2 (TXA2) causes bronchoconstriction, it is involved in the late asthmatic response (LAR), airway inflammation and BHR
Describe the role of platelet activating factor (PAF)
Mediation of bronchospasm, inflammation, anaphylaxis, sustained induction of BHR, oedema and chemotaxis of eosinophils. It is produced by neutrophils, monocytes and macrophages
How are leukotrienes fromed?
Arachadonic acid (AA) metabolized by 5-lipooxygenase (5-LO) to form leukotrienes (LTs). This pathway may lead to excess production of leukotrienes LTC4, LTD4 and LTE4, which produce bronchospasm and promote histamine release from mast cells, mucous secretion, microvascular permeability, airway oedema
For the most part prostaglandins are bad for asthmatics, with the exception of what?
Prostaglandin E1 and E2; they are bronchodilators (the reason we shouldn't give NSAIDs to patients with asthma, because it inhibits their production)
What are the clinical consequences of chronic airway inflammation
Increased bronchial hyper-responsiveness (BHR) to physical, chemical and pharmacological stimuli
Non-specific bronchial hyper-responsiveness and increased risk of exacerbations
Increased symptoms and worsening airways obstruction over days to weeks
Increased mucous production and thickening of mucous
Reduced clearance of the allergen from the mucosal lining of the airways
What is airway remodeling
Acute inflammation is how tissues respond to injury, leading to repair and restoration of the normal structure and function. However, asthma is a chronic inflammatory process of the airways that is subject to pathological healing. Airway structures may be altered leading to pathological remodelling, altered repair process leading to fibrosis and increase in smooth muscle cells and mucous glands
What are factors leading to varying degrees of airway obstruction?
Smooth muscle of airways
Neuronal control and neurogenic inflammation
Describe how mucous production contribute to airway obstruction
Mucous production is the lung's main defence against external pathogens and irritants. It is produced by goblet cells and bronchial epithelial tissue. Mucous in asthmatics tends to be more viscous (due to epithelial sloughing of cells and other factors) and it can't be expectorated (coughed/spit up). Bronchial glands are increased in size and goblet cells are increased in size and number in asthma
Describe how smooth muscles of the airways contribute to airway obstruction
They are wrapped around airways in spiral formation
Airway remodelling - muscle cell hypertrophy and hyperplasia.
In large airways of asthmatics, smooth muscle may account for 11% of wall thickness (normal is approximately 5%)
Describe how neuronal control and neurogenic inflammation contributes to airway obstruction
Airways innervated by sympathetic (NE), parasympathetic (ACh) and afferent sensory neurons (Glu). Cholinergic fibres release ACh, which act on muscarinic, causing bronchoconstriction. Adrenergic fibres release norepinephrine, which acts on alpha receptors, causing bronchoconstriction. Adrenergic fibres also release epinephrine, which acts on beta receptors, causing bronchodilation