Ocena wpływu hybrydy PK20 na nadreaktywność oskrzeli i proces zapalny w mysim modelu astmy nieatopowej

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Title: Ocena wpływu hybrydy PK20 na nadreaktywność oskrzeli i proces zapalny w mysim modelu astmy nieatopowej

Level of degree:

Degree discipline :

medical sciences

Degree grantor:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Abstract:

The exact mechanisms underlying the non-atopic asthma have not yet been fully elucidated. The purpose of the present study was the assessment of the anti-inflammatory potency of PK20 hybrid, comparison with the activity of the equimolar mixture of its both opioid and neurotensin pharmacophores and the refernce compound-dexamethasone, as well as a determination which of the hybrid structural elements stronger contribute to the observed effects (experiments with antagonists: naloxone hydrochlorode and SR 142948). The research was carried out in the mouse model of nonallergic asthma induced by the hapten. Balb/c mice were sensitized for two consecutive days, locally on the shaved skin of the abdomen and the inner surface of the paws, using dinitrofluorobenzene solution. After five days, contact with hapten occurred again via inratracheal instillation, resulting in the development of inflammation. After induction of inflammation, PK20 hybrid or othertested compounds were administred intraperitoneally. After 24 hours, airway hyperresponsveness was measured using nebulization of increasing doses of methacholine, followed by a collection of bronchoalveolar lavage fluid (BALF) and lungs for futher analyses.Based on the present study, it has been proved that the PK20 hybrid alleviates inflammmatory symptoms in the airways, such as: influx of inflammatory cells into BALF and lung tissue, increased expression of nuclear transcription factor NF-kB, proinflammatorycytokines production, increased concentration albumin in BALF and elevated level of mouse mast cell protease, malondiadehyde, secretory phospholipase A2 in lung homogenates. Additionally, the anti-inflammatory effect of the hybrid is comparable to dexamethasone activity. However,compared to dexamethasone, it is less effective in reducing airway hyperreactivity in response to methacholine nebulization. The hybrid compound has also stronger anti-inflammatory activity in comparison to an equimolar mixture of its two pharmacophores injected simultaneously. Activation of both opiod and neurotensin receptors seems to be necessary to induce the full anti-inflammatory effect of the tested chimera.t