Pathophysiology
A1AT is a glycoprotein mainly produced in the liver by hepatocytes, and, in some quantity, by enterocytes, monocytes, and macrophages. In a healthy lung, it functions as an inhibitor against neutrophil elastase, a neutral serine protease that controls lung elastolytic activity which stimulates mucus secretion and CXCL8 release from epithelial cells that perpetuate the inflammatory state. With A1AT deficiency, neutrophil elastase can disrupt elastin and components of the alveolar wall of the lung that may lead to emphysema, and hypersecretion of mucus can develop chronic bronchitis. Both conditions are the makeup of chronic obstructive pulmonary disease (COPD).Normal blood levels of alpha-1 antitrypsin may vary with analytical method but are typically around 1.0-2.7 g/L. In individuals with PiSS, PiMZ and PiSZ genotypes, blood levels of A1AT are reduced to between 40 and 60% of normal levels; this is usually sufficient to protect the lungs from the effects of elastase in people who do not smoke. However, in individuals with the PiZZ genotype, A1AT levels are less than 15% of normal, and they are likely to develop panlobular emphysema at a young age. Cigarette smoke is especially harmful to individuals with A1AD. In addition to increasing the inflammatory reaction in the airways, cigarette smoke directly inactivates alpha-1 antitrypsin by oxidizing essential methionine residues to sulfoxide forms, decreasing the enzyme activity by a factor of 2,000.With A1AT deficiency, the pathogenesis of the lung disease is different from that of the liver disease, which is caused by the accumulation of abnormal A1AT proteins in the liver, resulting in liver damage.
Acetylcholine then binds to M2 muscarinic receptors, causing the decrease in heart rate that is referred to as reflex bradycardia.The M2 muscarinic receptors decrease the heart rate by inhibiting depolarization of the sinoatrial node via Gi protein-coupled receptors and through modulation of muscarinic potassium channels. Additionally, M2 receptors reduce the contractile forces of the atrial cardiac muscle and reduce the conduction velocity of the atrioventricular node (AV node). However, M2 receptors have no effect on the contractile forces of the ventricular muscle.Stimuli causing reflex bradycardia include:

Oculocardiac reflex
Sympathetic response to intracranial hypertension
Systemically administered norepinephrine (α-adrenergic effects on systemic vasculature exceed the effects of β1-adrenergic effects on the heart)


== References ==