2016 Section 5 Green Book

Stachler

Inflammatory mechanisms Local inflammation occurs when an inhaled antigen causes an IgE-mediated type 1 hypersensitivity reaction. This ini- tiates an inflammatory cascade, characterized by mast cell degranulation. Preformed mediators including histamine, kinins, and proteases are released, which causes chemotaxis and migration of other sensitized mast cells, neutrophils, basophils, eosinophils, T lymphocytes, and macrophages across a mucosal endothelium into the local area (nose or bronchial mucosa) and submucosa. Vascular leakage and interstitial edema occur, causing pruritis, rhinorrhea, nasal congestion, and sneezing. 46 This response is linked by up- regulated systemwide inflammatory mediators at distal sites in the respiratory tract (lined by pseudostratified colum- nar epithelium). 41,47–49 Braunstal et al. 41,48,49 and Geor- gopoulos et al. 47 noted in a series of studies that antigens placed in the nose resulted in upregulation of inflamma- tory mediators in the distal bronchi. Similarly, they noted that antigen placement into the bronchi with a broncho- scope resulted in upregulation of inflammatory mediators in the nose. Interactions between inflammatory cells, mast cells, alveolar macrophages, eosinophils, lymphocytes, neu- trophils, basophils and associated mediators, histamine, leukotrienes, prostaglandin D 2 , and platelet-activating fac- tor cause bronchial smooth muscle contraction. 7,50 This late-phase response will occur several hours after an initial response because it requires an influx of inflammatory cells and can lead to chronic changes. The eosinophils seem to have the greatest increase in proportion to other inflamma- tory cells in this timeframe. 50,51 These reactions show that allergic changes in one area can effect the whole unified airway. This links the allergic reactions to distal locations in the unified airway. Eosinophils and their release of their cationic pro- teins (major basic protein [MBP], eosinophil cationic protein [ECP], peroxidase, and eosinophil-derived neurotoxin [EDN]) is the cardinal feature of allergic pathophysiology. 52–54 The eosinophil is drawn to the inflammatory reaction by the T helper 2 (TH2) cy- tokine interleukin 5 (IL-5). 55 IL-5 mediates eosinophil expansion, priming, recruitment, and prolonged tissue survival in allergic reactions. 55 IL-5, IL-4, IL-13, and eotaxins (eosinophil-specific chemokines) are responsible for promoting the eosinophil-mediated inflammatory responses. 55 Endothelial adhesion proteins, intercellular adhesion molecule-1 (ICAM-1), and vascular cell ad- hesion molecule-1 (VCAM1) assist in the migration of neutrophils, lymphocytes, and eosinophils from the in- travascular space into the airway. 50,56–59 Other cells in the inflammatory process, mast cells, release their mediators and histamine causing leukotrienes to be created, which cause bronchoconstriction. The eosinophil release of the toxic proteins causes endothelial cell damage and airflow obstruction. 50 Histologically, these processes create the mucosal edema, submucosal gland and bronchial smooth muscle hypertrophy, mucous hypersecretion, basement

membrane thickening, and fibrosis classically seen in asthma. 50,60–62

Systemic, neurogenic mechanisms Neuronal stimulation in the nose can result in the re- lease of cholinergic neurotransmitters and contraction of the bronchial smooth muscle. 63,64 This reaction links a lo- cal response to a systemic, distal location. Furthermore, there is strong evidence that links the distribution of in- flammatory mediators from an initial inflammatory site to lymphoid tissue 65 and marrow, amplifying the inflam- matory responses across the nasal passages, sinuses, and lower airways. Increased blood eosinophil and IL-5 levels in the upper and lower airways were shown when a single antigen challenge was administered to nonasthmatic sub- jects with seasonal allergy. 66 Bronchial hyperresponsive- ness was noted when atopic patients with AR and asthma were given a nasal challenge. 67 Nasal challenges in aller- gic patients without asthma resulted in increased bronchial expression of adhesion molecules (VCAM-1, ICAM-1, and endothelial-leukocyte adhesion molecule 1). As discussed previously in the inflammatory mechanisms section, these molecules are responsible for assisting in the transport of the eosinophil from the circulation into the airway, reduc- ing the peak expiratory airflow 41 as the numbers of the cells in the area increase and the inflammation from the reaction begins to augment. Bronchial challenge with antigens, in nonasthmatic, al- lergic patients, resulted in an intense nasal inflammatory reaction causing immune cell degranulation, and increased IL-5 levels in peripheral blood. 49 This suggests that stimu- lation can occur anywhere within the unified airway. Neuroregulatory mechanisms from vagal nerve acti- vation may cause bronchoconstriction of the bronchial smooth muscle. Neuromediators, substance P and calci- tonin gene–related peptide, modulate the release of his- tamine and bradykinin, which cause unrestricted passage of proteins and fluid through the vascular epithelium. Di- rect cholinergic neurotransmitter release may cause stimu- lation of the bronchial smooth muscle. 68–70 The results is bronchoconstriction, which is a defining characteristic of asthma. Chronicity of asthma Asthma is a chronic disease of the lower airways that has 3 defining characteristics: (1) airway inflammation; (2) re- versible airway obstruction, in most cases; and (3) increased airway responsiveness to extrinsic stimuli. 71 The inflamma- tion that is the hallmark of asthma may be present for many years and is undetectable until the symptoms of asthma be- gin to appear. As described previously, in the prior two sections, the eosinophil appears to be the key inflamma- tory cell in the destructive process at the cellular level. The chronic inflammation that develops causes airway

International Forum of Allergy & Rhinology, Vol. 5, No. S1, September 2015

211