Inherent tone of human bronchus: role of eicosanoids and the epithelium

Abstract

1 Airway preparations of dierent species possess varying degrees of inherent tone which is the result of dierent metabolites of arachidonic acid in dierent species. In human bronchial smooth muscle in vitro we have investigated the eects of 5-lipoxygenase inhibition (zileuton, 10 mM), cyclo-oxygenase inhibition (indomethacin, 1 mM) and mechanical epithelium removal on inherent tone. The shunting of arachidonic acid by inhibition of one or other of these enzymes, as a possible explanation for the eects observed, has also been investigated. 2 Zileuton caused a signi®cant fall in tone either alone (7107+33 mg) or after cyclo-oxygenase inhibition (7203+48 mg) and this eect was not signi®cantly altered by epithelial removal (7191+43 mg alone; 7333+88 mg after indomethacin). Indomethacin increased tone when applied alone (160+94 mg), but this eect only reached statistical signi®cance after 5-lipoxygenase inhibition, (210+81 mg; P50.05). Epithelial removal did not alter the eect of indomethacin when applied alone (213+97 mg), but signi®cantly reduced the eect of indomethacin after 5-lipoxygenase inhibition (34+23 mg; P50.05). 3 These data suggest that inherent tone in human bronchus is largely the result of contractile 5-lipoxygenase products. However, the involvement of cyclo-oxygenase products cannot entirely be discounted, since in the presence of 5-lipoxygenase inhibition contractile and relaxant eicosanoids originating from the bronchial epithelium appear to in¯uence signi®cantly inherent tone.

Mechanisms of intrinsic force in small human airways

“…Finally, our study is similar to a prior study by Watson et al and finds the influence of the bronchial epithelium on human airway IF and active tension to be very limited (Watson et al, 1997). This result differs from guinea pig trachea where spontaneous force has been clearly determined to depend upon constitutively derived airway epithelial prostaglandin synthesis (Orehek et al, 1975).…”

Studying human airway pharmacology in microsections: application of videomicrometry

“…The development of spontaneous narrowing was unaffected by the cyclooxygenase inhibitor, indomethacin, ruling out prostanoids as the major mediators. This finding contrasts with the spontaneous, prostanoidmediated luminal narrowing observed in the guinea pig trachea under the same conditions [3] and the absence of spontaneous narrowing of epitheliumintact human airways under isometric conditions in the organ bath [11]. This suggests that human airway epithelial cells generate mediators that increase airway tone.…”

The role of leukotrienes in allergic diseases

“…165 CysLTs increase the production of certain cytokines and vice versa. The LTRA, pranlukast, significantly reduces the production of IL-4, IL-5, and GM-CSF by PBMCs upon allergen induction.…”