The mechanisms leading to asthma, and those guarding against it, are yet to be fully defined. The neuropeptide VIP is a cotransmitter, together with nitric oxide (NO), of airway relaxation, and a modulator of immune and inflammatory responses. NO-storing molecules in the lung were recently shown to modulate airway reactivity and were proposed to have a protective role against the disease. We report here that mice with targeted deletion of the VIP gene spontaneously exhibit airway hyperresponsiveness to the cholinergic agonist methacholine as well as peribronchiolar and perivascular cellular infiltrates and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid. Immunologic sensitization and challenge with ovalbumin generally enhanced the airway hyperresponsiveness and airway inflammation in all mice. Intraperitoneal administration of VIP over a 2-wk period in knockout mice virtually eliminated the airway hyperresponsiveness and reduced the airway inflammation in previously sensitized and challenged mice. The findings suggest that 1) VIP may be an important component of endogenous anti-asthma mechanisms, 2) deficiency of the VIP gene may predispose to asthma pathogenesis, and 3) treatment with VIP or a suitable agonist may offer potentially effective replacement therapy for this disease.

Hypoxic pulmonary vasoconstriction underlies the development of high-altitude pulmonary edema. Anecdotal observations suggest a beneficial effect of garlic in preventing high-altitude symptoms. To determine whether garlic influences pulmonary vasoconstriction, we assessed the effect of garlic on pulmonary pressures in rats subjected to alveolar hypoxia and on vasoconstriction in isolated pulmonary arterial rings. Garlic gavage (100 mg/kg body wt) for 5 days resulted in complete inhibition of acute hypoxic pulmonary vasoconstriction compared with the control group. No difference in mean arterial pressure or heart rate response to hypoxia was seen between the groups. Garlic solution resulted in a significant dose-dependent vasorelaxation in both endothelium-intact and mechanically endothelium-disrupted pulmonary arterial rings. The administration of N G-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor) inhibited the vasodilatory effect of garlic by 80%. These studies document that garlic blocks hypoxic pulmonary hypertension in vivo and demonstrate a combination of endothelium-dependent and -independent mechanisms for the effect in pulmonary arterial rings.

1. The aims of the present study were to investigate the effects of fresh garlic and one of its active metabolites, allicin, on rat isolated pulmonary arteries (RPA). 2. In endothelium-intact and phenylephrine-precontracted RPA, the addition of a water or a 5% ethanol extract of fresh garlic (1-500 microg/mL) resulted in a dose-dependent relaxation reaching a maximum (mean +/- SEM) of -91 +/- 3 and -93 +/- 2%, respectively, with an ED(50) of 113 +/- 12 and 106 +/- 10 microg/mL, respectively. The vasorelaxation was readily reversible upon washing and no tachyphylaxis was noted. 3. An extract of the external garlic storage leaf produced a significantly greater relaxation than the inner stem. Microfiltration of extracts with a 10,000 molecular sieve did not attenuate relaxation. Inactivation of alliinase and allicin formation, with either boiling of the garlic clove for 30 min or 100% ethanol treatment, completely abolished relaxation. In contrast, similar treatment of crushed garlic with formed allicin retained the relaxation response. 4. Pure allicin produced a similar relaxation as garlic extract, with an EC(50) of approximately 0.8 microg/mL. Disruption of endothelium or N(G)-nitro-L-arginine methyl ester pretreatment attenuated the relaxation, whereas indomethacin had no effect. 5. Prior garlic (500 microg/mL) treatment enhanced acetylcholine relaxation by shifting the response curve to the left, but had no effect on nitric oxide (NO) donor-induced responses. 6. These results demonstrate that garlic and the active metabolite allicin are capable of eliciting a NO-dependent relaxation in RPA and that this response is likely to be mediated via garlic activation of NO formation rather than its stabilization.

No abstract

No abstract