Asthma

HOW DOES ASTHMA PRESENT?

The clinical hallmarks of asthma are coughing, shortness of breath, wheezing, and chest tightness.  These symptoms are associated with the contraction of airway smooth muscle, mucosal thickening from edema and cellular infiltration, and inspissaton (thickening) of mucus plugs (such as the one we saw in the previous path lecture; picture on left) into the lumen of the lung airways. 

WHAT IS ASTHMA?

Asthma used to be considered an obstruction of airways that reverses with time and treatment, but is now considered a disease of chronic inflammation.  So, the focus on asthma treatment is now on the long term management of chronic inflammation.  This inflammation involves the recruitment and activation of eosinophils and release of cytokines which change airway morphology.  The (usually reversible) changes in airway morphology include: increased muscle mass, subepithelial fibrosis, edema, and epithelial cell damage

 These changes in airway morphology ultimately result in bronchial hyperresponsiveness and constriction.  Bronchial hyperresponsiveness (a result of the inflammation) is defined as the increased responsiveness of the trachea and bronchi to the following: allergens, exercise, aspirin, cold air, and chemicals. 

HOW DO PHYSICIANS DIAGNOSE ASTHMA?  

If asthma is suspected, use the following to diagnose the patient:

·         Changes in forced expiratory volume (FEV)

o        Record lung volume expelled in 1 sec to volume expelled in 3 sec, and plot these points; the slope of this line is a measure of the person’s ability to expel air. 

o        The slope of this line decreases dramatically in asthma!  This decrease in slope is even more significant when an asthmatic is challenged with methylcholine (methylcholine can be used for asthma diagnosis). 

WHAT CAUSES ASTHMA, AND WHAT CAUSES THE SYMPTOMS?

Common allergens that can cause asthma include seasonal irritants such as ragweed and year round allergens such as dust mites and domestic pets. 
 

   These allergens bind to IgE antibodies, and these IgEs bind to mast cells, which causes immediate release of granule contents, a slightly delayed release (over minutes) of lipid mediators, and a late release (over hours) of cytokines.

o                          The immediate release of the mast cell granule contents histamine, TNF, proteases and heparin causes symptoms such as sneezing, nasal congestion, itchy runny nose, and watery eyes.

o        The over minutes release of lipid mediators prostaglandins and leukotrienes causes wheezing and bronchoconstriction (the granule contents also contribute to this).

o        The over hours release of cytokines specifically IL-4 and IL-13 causes mucus production and eosinophil recruitment.

It has been shown that as serum IgE levels increase, the odds of an asthmatic episode also increase.  This makes sense given what we have just learned about the role of IgE immunoglobulin role in the release of inflammatory mediators.   

* Although we have just been talking about antigenic causes of bronchospasm, keep in mind that bronchospasm can also be due to non antigenic causes such as cigarette smoke, cold air, exercise, distilled water, and viruses!!

Now we know that the granule contents and lipid mediators of the mast cell response to allergens and non-antigentic causes can cause bronchospasm.  How exactly, though, does bronchospasm/bronchoconstriction happen? 

HOW DOES THE BRONCHOCONSTRICTIVE REFLEX WORK?

 -          so the inhaled irritant (the stars to the right of the mucosa) could be either an inhaled irritant or cold air (an example of a non-antigen).

-          The vagal afferent nerves sense the presence of this irritant, and the pregangliconic fiber of the vagal efferent nerve transmits Ach to the ganglion via nicotinic receptor. The postganglionic nerve gets Ach to the smooth muscle via muscarinic receptor, and reflex bronchoconstriction ensues.

-             The caption for this diagram from the lecture outline states this a bit more eloquently, and adds to the amount of information presented in class: The airway is represented microscopically by a cross-section of the wall with branching vagal sensory endings lying adjacent to the lumen. Afferent pathways in the vagus nerves travel to the central nervous system; efferent pathways from the central nervous system travel to efferent ganglia. Postganglionic fibers release ACh, which binds to muscarinic receptors on airway smooth muscle. Inhaled materials may provoke bronchoconstriction by several possible mechanisms. First, they may trigger the release of chemical mediators from mast cells. Second, they may stimulate afferent receptors to initiate reflex bronchoconstriction or to release tachykinins (eg, substance P) that directly stimulate smooth muscle contraction.

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