Leukotriene D₄(LTD₄) Induces Mucus Secretion from Goblet Cells in the Guinea Pig Respiratory Epithelium

Abstract

To study the potential role of leukotriene (LTD4) as a mucus secretagogue, anesthetized and spontaneously breathing guinea pigs were intubated and challenged with various concentrations of an LTD4 aerosol. The resulting changes in airway resistance and compliance were then observed for 20 min, after which the animals were euthanized and the lower respiratory tract airways fixed for morphometric evaluation. Sections for these airways were stained with alcian blue-periodic acid Schiff (AB-PAS), photographed, and the content of AB-PAS positive granules in the epithelium of the extrapulmonary bronchi quantified. The fractional volume of mucus granules in the respiratory epithelial volume. Aerosol LTD4 produced a dose-dependent decrease in the granule fractional volume (GFV) over the range of 0.1 to 1 microgram/ml when compared with epithelia challenged with saline aerosols. Increasing the concentration of administered LTD4 from 1 microgram to 3 micrograms/ml produced further bronchoconstriction but had no further effect on the GFV. Decreases in GFV did not appear to be secondary to smooth muscle contraction since aerosols of other agonists (0.05% histamine and 1% acetylcholine), which yielded resistance changes similar to those of LTD4, did not effect the GFV. Pretreatment with an aerosol of the specific LTD4 receptor antagonist SK&F 104353-Z2 produced a dose-dependent inhibition of the changes in both the airway resistance and GFV. The data suggest that LTD4 mediates epithelial mucus secretion as well as bronchoconstriction in the guinea pig airway and may provide an additional therapeutic use for specific LTD4 receptor antagonists in the treatment of obstructive pulmonary disease.

Role of leukotrienes in asthma pathophysiology

“…In animal models, CysLTs increased mucus production from both submucosal glands and epithelial goblet cells. 62,63 However, these data were apparently contradicted by our findings that LTD 4 is involved in altering nasal mucosal blood flow and does not increase nasal secretions. 33 Also, none of the studies on the effects of inhaled CysLT reported an increased airway secretion in the study patients.…”

Exposure to Diesel Exhaust Exacerbates Allergen-induced Airway Responses in Guinea Pigs

“…Morphologic and morphometric findings suggested that mucus hypersecretion was due at least in part to the secretion from goblet cells. Many inducers of airway goblet cell secretion have been reported, including lipid mediators (14,15), a cholinergic agonist (16), substance P (17), and cytokines (18)(19)(20). Among these inducers, interleukin-4 (IL-4) has been shown to play an important role in both goblet cell metaplasia and mucus hypersecretion (18,19).…”

Continuity of airway goblet cells and intraluminal mucus in the airways of patients with bronchial asthma

“…It has been shown [23] that goblet cell mucin secretion is not under any pharmacological control [23]; and some investigators have indicated that airway goblet cells are unresponsive to β-adrenergic and cholinergic stimuli [24,25]. In contrast, leukotriene D 4 is reported to induce secretion of mucus from airway goblet cells in guinea-pig in vivo [26]. Cultured goblet cells secrete mucins continuously, probably by a constitutive pathway [27], a pathway similar to intestinal goblet cells [28].…”