Leukotrienes

Excess production of leukotrienes [def] promotes the inappropriate response to harmless antigenic substances that characterizes allergy. Leukotrienes [def] are:

  • fatty acid-derived inflammatory mediators that play a significant role in the pathophysiology of allergic diseases, including asthma, atopic dermatitis, and allergic rhinitis
  • derived from the fatty acid arachidonic acid (AA), which is concentrated in the membrane phospholipids of blood cells
  • synthesized by circulating immune cells in response to a stimulus such as allergen exposure

THE LEUKOTRIENE PATHWAY AND METABOLISM OF ARACHIDONIC ACID

SUPPORTING DOCUMENTATION FOR PHYSICIANS:

 

ROLES OF LEUKOTRIENES

LTB4

LTB4 is produced primarily by neutrophils and monocyte/macrophages (12, 20). The role of LTB4 in allergic disease is multifactorial. First, LTB4 activates neutrophils leading to endothelial leakage which further promotes allergic inflammation (7, 20).

CYSTEINYL LEUKOTRIENES

The roles of the cysteinyl leukotrienes, LTC4, LTD4 and LTE4, are multifaceted (23). When produced in lung tissue, they are powerful bronchoconstrictors; LTC4, LTD4 for example, are ca. 1000x more powerful than histamine (23). Cysteinyl leukotrienes are produced by resident mast cells and alveolar macrophages, as well as by peripheral blood eosinophils (23, 24). When produced in sinuses, cysteinyl leukotrienes promote the production of mucous, promote cell-mediated inflammation and promote synthesis of inflammatory cytokines (7, 13, 23). Airborne allergen exposure provokes leukotriene synthesis in nasal tissues (6). Cysteinyl leukotrienes also promote sensitivity to histamine by immune cells (25). In skin, these leukotrienes increase the permeability of vascular tissue to inflammatory cells, and epidermal cells are sites of leukotriene synthesis (26). In all of these allergic diseases, there is an overproduction of leukotrienes: the specific disease(s) present in any one individual may be determined in part by the location(s) of leukotriene synthesis.

LEUKOTRIENES IN ALLERGIC RHINITIS

The cysteinyl leukotrienes are potent bronchoconstrictors produced by immune cells resident in lung tissue. These mediators are direct causal agents of many of the symptoms of asthma, including airway smooth muscle constriction, airway hyperresponsiveness, eosinophil migration, vascular permeability, and edema (5, 7, 8, 10, 12, 20). Leukocytes from asthmatics produce 3 – 5x higher levels of leukotrienes than do leukocytes from healthy controls (14). The 5-LO enzyme may be upregulated in asthmatic subjects (11). Further, the response to inhaled leukotrienes is exaggerated in asthmatics compared to healthy subjects (12). In asthmatic children, concentrations of cysteinyl leukotrienes in exhaled breath condensates were significantly higher than in control children (2, 21, 22). Asthmatic children with exercise-induced bronchoconstriciton (EIB) had higher concentrations of cysteinyl leukotrienes in exhaled breath condensates than control children or asthmatic children without EIB (9). Exaggerated production of cysteinyl leukotrienes is also evident in aspirin-induced asthma (1).

LEUKOTRIENES IN ALLERGIC RHINITIS

Leukotrienes mediate many of the typical symptoms of allergic rhinitis, including nasal congestion, mucous secretion and edema (8, 13). CysLTs are overproduced by patients with allergic rhinitis within minutes of nasal allergen exposure (13). Increased production of LTC4 in vivo has been reported in the tear fluid (4) and intact skin (19) of atopic patients after allergen specific challenge. These lipid mediators interact with receptors, particularly the cysLT1 receptor, on eosinophils, mast cells, macrophages, and neutrophils (16). They also stimulate production of other proinflammatory mediators, such as cytokines IL-4 and IL-5 (16). Peters-Golden and Henderson (13) recently reviewed the significant role that leukotrienes play in allergic rhinitis. "Many of the cells involved in the pathophysiology of allergic rhinitis produce and release CysLTs. This production and release begin early in the allergic response, since unlike cytokines, which require transcription and translation before synthesis, all the enzymes necessary to produce CysLTs are already present in inflammatory cells. During the early phase response, mast cells and basophils are the primary source of CysLTs, which act both locally and systemically to stimulate the production, recruitment, and activation of additional inflammatory cells. The newly recruited inflammatory cells, predominantly eosinophils but also monocytes and macrophages, are the primary source of CysLTs during the late-phase reaction".