Asthma

Asthma is chronic constriction and inflammation of the airways of the lungs. Aggrevation of these symptoms can result from allergens, exercise, stress or infection. Once lungs become asthmatic the episodes of symptoms can be controlled by drugs that usually include broncodilators. But what is the cause of asthma?

Risk factors suggest the source of the disease. Exposure to smoke or inhaled pollutants, antibiotic use, formula use, obesity (metabolic syndrome), use of chlorinated swimming pools all increase the likelihood of developing asthma. The common factor in all of the risks is chronic systemic inflammation combined with some irritation of the lungs. Systemic inflammation of asthmatics is frequently the result of altered gut flora. Use of formula or antibiotics, for example, lead to a disruption of normal newborn gut bacteria, replacement with hospital strains, e.g. Clostridia spp., and inflammation. Obesity can also lead to inflammatory gut flora. Systemic inflammation combined with lung irritants, e.g. allergens, chlorinated organic compounds, infections, can lead to allergic responses and in the lung this can mean asthma.

An asthmatic attack starts with spasmodic contraction of the airway muscles, followed by inflammation. Initially, so called cholinergic receptors located in the membranes of the smooth muscles that surround the airways of the lungs, are stimulated by the binding of neurotransmitters. The result is that these receptors trigger the cleavage of phosphoinositol diglycerides to release inositol with three phosphates (IP3) and a glycerol with two lipid chains (diacylglycerol, DAG). The IP3 (which mimics heparin, by the way) binds to receptors controlling the internal stores of calcium (in the endoplasmic reticulum), causing a surge of intracellular calcium. The rise in intracelllular calcium is what causes the muscle cell actin and myosin to contract and the rings of muscle on the airways to constrict. This is ridiculously simplified to show the basic components of stimulating receptors, IP3 increase, calcium increase and muscle contraction.

Early attempts to treat asthma used plant extracts that blocked the action of the cholinergic (as in acetylcholine) receptors. These are familiar plants such as tobacco, coffee, tea and cacao. The cholinergic blockers are nicotine (pictured and in computational model below), caffeine, theophylline and theobromine. Datura stramonium, Jimson weed, also produces atropine, that is another cholinergic inhibitor. There are modern forms of the cholinergic antagonists, which are used to treat episodic constriction.

I have illustrated in the model above, how nicotine binds to the cholinergic receptor, between a tryptophan (bottom, yellow) and two tyrosines (above, orange).

The IP3-calcium constriction system can also be stimulated by allergen-based mast cell release of histamine. The histamine binds to another set of receptors and triggers IP3 release. In this context, anti-histamines are moderately effective, but the initial response is so rapid, that the histamine phase is quickly passed.

The rapid constriction phase is followed six to eight hours later by inflammatory release of leukotrienes that also cause constriction via IP3. Leukotrienes share the same precursor, omega-6 arachidonic acid, as the inflammatory prostaglandins made by the cyclooxygenase, COX 1&2, but in this case an alternative enzyme, lipoxygenase, is used. The leukotriene receptors on muscle cells act similarly to the catechol receptors and stimulate constriction.

Another approach to preventing constriction or actively relaxing airway smooth muscles is by stimulation of adrenergic receptors that have the opposite effect of cholinergic receptors. The adrenergic receptors trigger cyclic AMP production, that compromises the IP3-calcium signaling. Cholinergic receptors are activated to minimize the damage to inhaled toxins or irritants. Adrenergic receptors open the airways to increase airway capacity for flight or fight in response to adrenalin. Some of the drugs to treat asthma stimulate adrenergic receptors and open airways.

Treatment of asthma is centered on constriction episodes and not on reversal or prevention of the disease. Thus, treatment or prevention of an asthmatic episode of airway constriction can utilize drugs that block steps along the cholinergic cascade (receptor, IP3 increase, calcium increase) or by stimulation of adrenergic receptors.

These treatments do not address the cause or reversal of asthma. The inflammatory basis of most asthma risk factors suggests that lowering chronic inflammation, particularly in young children, should be a high priority in preventing asthma. The association of asthma with the use of formula and antibiotics, implicates inflammation, as well as inflammatory gut flora, as the foundations of asthma and emphasizes the essential role of diet and lifestyle in the development of asthma.