Cysteinyl leukotrienes (CysLTs) are potent lipid signaling molecules that are a component of inflammatory and allergic reactions. Derived from fatty acids in the membranes of immune cells, these molecules are synthesized and released in response to triggers like allergens or tissue injury. Once released, CysLTs travel to nearby cells and bind to specific surface receptors, initiating a cascade of biological effects. Their actions on blood vessels, smooth muscles, and other immune cells contribute to the physiological changes that characterize many inflammatory diseases.
The Biological Origin of Cysteinyl Leukotrienes
Cysteinyl leukotrienes are not stored within cells but are created when needed. The process begins with arachidonic acid, an omega-6 fatty acid that is a component of cell membranes, particularly in inflammatory cells like mast cells, basophils, and eosinophils. When a cell is activated by a stimulus, an enzyme called phospholipase A2 releases arachidonic acid from the membrane.
The free arachidonic acid is then acted upon by the 5-lipoxygenase (5-LOX) enzyme. This enzyme, along with a helper protein called 5-lipoxygenase-activating protein (FLAP), is the primary switch for leukotriene production. This process converts arachidonic acid into an unstable intermediate, leukotriene A4 (LTA4).
From this point, the pathway diverges. In certain cells, LTA4 is combined with glutathione to form leukotriene C4 (LTC4), the first of the cysteinyl leukotrienes. LTC4 is then transported out of the cell, where it can be modified by enzymes into two other active forms: leukotriene D4 (LTD4) and leukotriene E4 (LTE4). Together, LTC4, LTD4, and LTE4 make up the family of CysLTs.
The Role in Inflammation and Allergic Reactions
Cysteinyl leukotrienes contribute to the signs of inflammation and allergic reactions through several primary actions. These molecules are up to 1,000 times more potent than histamine at causing some of these effects.
- Bronchoconstriction: They cause the tightening of smooth muscles lining the lungs’ airways, which narrows the air passages and can lead to breathing difficulties.
- Increased vascular permeability: They act on cells lining small blood vessels, causing them to create gaps. This allows fluid to escape from the bloodstream into surrounding tissues, resulting in edema, or swelling.
- Mucus overproduction: They stimulate specialized cells in the respiratory lining to secrete thick mucus, which can obstruct airways and impair the function of cilia, the hair-like structures that clear debris from the lungs.
- Immune cell recruitment: They act as chemical signals (chemoattractants) that recruit other immune cells, like eosinophils, to the site of inflammation, which amplifies the inflammatory cascade as these new cells release their own mediators.
Association with Specific Medical Conditions
The physiological actions of cysteinyl leukotrienes are directly linked to the symptoms of several common medical conditions. In asthma, their effects cause bronchoconstriction, mucus production, and airway swelling, which lead to wheezing, coughing, and chest tightness. Patients with asthma often have elevated levels of CysLTs in their airways.
Allergic rhinitis, commonly known as hay fever, is another condition heavily influenced by CysLTs. When an allergen triggers their release in the nasal passages, the resulting vascular permeability and mucus secretion cause nasal congestion and a runny nose.
The influence of CysLTs extends to other inflammatory disorders. They are implicated in chronic urticaria (hives), where increased vascular permeability contributes to swollen, itchy welts on the skin. They may also play a role in atopic dermatitis (eczema).
Therapeutic Targeting of Cysteinyl Leukotrienes
Understanding how CysLTs cause symptoms led to the development of targeted therapies. CysLTs exert their effects by binding to specific proteins on cell surfaces, known as CysLT receptors. The primary receptor involved is the cysteinyl leukotriene receptor 1 (CysLT1), found on airway smooth muscle and inflammatory cells. When CysLTs bind to this receptor, they activate the cell’s inflammatory response.
To counteract this, a class of drugs known as leukotriene receptor antagonists (LTRAs), including medications like montelukast and zafirlukast, was developed. These drugs selectively bind to the CysLT1 receptor without activating it. By occupying the receptor’s docking site, they physically block CysLTs from binding and initiating the inflammatory cascade.
This mechanism can be compared to placing a blank key into a lock; it fits and blocks the lock, but it cannot turn it to open the door. This prevents the “real” key (the cysteinyl leukotriene) from gaining access.
By inhibiting the actions of CysLTs at the receptor level, LTRAs effectively reduce bronchoconstriction, airway edema, and mucus secretion. This provides a strategy for managing the chronic symptoms of conditions like asthma and allergic rhinitis.