Cysteinyl leukotrienes (CysLTs) are lipid compounds that function as chemical messengers in the body’s inflammatory response. Produced by immune cells in response to triggers like allergens, they are part of the immune system designed to protect the body from perceived threats. Their actions, however, are a primary cause of the symptoms associated with allergic reactions and asthma.
The Formation of Cysteinyl Leukotrienes
The synthesis of cysteinyl leukotrienes begins with arachidonic acid, a fatty acid released from cell membranes during an inflammatory event. This process is initiated by the activation of an enzyme known as 5-lipoxygenase (5-LO). The 5-LO enzyme acts on arachidonic acid, converting it into an unstable intermediate molecule called leukotriene A4 (LTA4).
This production occurs predominantly within specific immune cells, including mast cells, eosinophils, and basophils. These white blood cells are central to allergic and inflammatory responses. Inside these cells, LTC4 synthase converts the LTA4 intermediate into leukotriene C4 (LTC4), the first of the cysteinyl leukotrienes.
Once produced, LTC4 is transported outside the cell where it undergoes further modification by enzymes. These enzymes sequentially convert LTC4 into two other active forms: leukotriene D4 (LTD4) and leukotriene E4 (LTE4). LTC4, LTD4, and LTE4 together make up the family of CysLTs.
Physiological Effects in the Body
Once released, cysteinyl leukotrienes exert effects by binding to specific receptors on target cells, primarily the CysLT1 and CysLT2 receptors. One of their main actions is causing smooth muscle contraction. In the respiratory system, CysLTs trigger constriction of the muscles lining the airways, an effect known as bronchoconstriction, which narrows air passages and can make breathing difficult.
CysLTs also stimulate mucus secretion in the respiratory tract. Glands are prompted to increase their output, leading to thicker mucus in the airways. While this response is intended to trap foreign particles, excessive production can clog smaller bronchioles, contributing to congestion and coughing.
CysLTs also enhance the permeability of small blood vessels. They cause endothelial cells that form vessel walls to pull apart slightly, allowing fluid from the blood to leak into surrounding tissues. This fluid accumulation results in tissue swelling, or edema. In the airways, this swelling can further narrow the passages.
These molecules also act as chemoattractants, orchestrating a broader inflammatory response. They recruit other immune cells, particularly eosinophils, to the site of inflammation. This influx of inflammatory cells can amplify and sustain the reaction, potentially leading to chronic inflammation if not properly regulated.
Role in Allergic and Inflammatory Diseases
The physiological actions of CysLTs are responsible for the symptoms of several allergic and inflammatory diseases. In asthma, the bronchoconstriction they induce leads to wheezing, chest tightness, and shortness of breath. The increased mucus production and vascular leakage contribute to the cough, congestion, and airway obstruction common in an asthma attack.
Allergic rhinitis, or hay fever, is another condition influenced by CysLTs. When a person with allergies inhales a trigger like pollen, mast cells in the nasal passages release these mediators. This release increases blood vessel permeability in the nasal lining, leading to swelling and congestion, while increased mucus secretion results in a runny nose.
Beyond the respiratory system, CysLTs are implicated in other inflammatory conditions like atopic dermatitis, a type of eczema. These mediators are believed to contribute to skin inflammation and itchiness. Their ability to increase vascular permeability and attract inflammatory cells is a factor in the development of the red, itchy rashes associated with the condition.
These mediators are also involved in aspirin-exacerbated respiratory disease (AERD). In individuals with AERD, taking aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) leads to an overproduction of CysLTs. This surge results in severe asthma attacks and nasal congestion, demonstrating a direct link between CysLT synthesis and respiratory symptoms in susceptible individuals.
Medical Management and Therapeutic Targeting
Medical interventions counteract the effects of cysteinyl leukotrienes. The most common class of drugs is leukotriene receptor antagonists (LTRAs), which work by selectively blocking the CysLT1 receptor. This is the primary receptor through which CysLTs exert their pro-inflammatory effects. By occupying this receptor, LTRAs prevent CysLTs from binding and initiating the signals that lead to bronchoconstriction and inflammation.
Commonly prescribed LTRAs include montelukast and zafirlukast. These oral medications are used as a maintenance therapy for asthma and allergic rhinitis. They help control symptoms by preventing the airway muscle contraction and mucus production caused by CysLTs, offering a focused approach to managing these respiratory diseases.
A different therapeutic strategy involves inhibiting leukotriene production altogether. This approach targets the 5-lipoxygenase (5-LO) enzyme, which is responsible for the initial step in their synthesis. Drugs like zileuton are 5-LO inhibitors, shutting down the production of LTA4 and consequently the entire family of leukotrienes.
This inhibition of synthesis provides a broader blockade of the pathway compared to receptor antagonists. While LTRAs block the action of existing CysLTs, synthesis inhibitors prevent them from being created. The choice between an LTRA and a synthesis inhibitor depends on the specific clinical situation and the patient’s response to treatment.