激素增强收缩的支气管平滑肌再伸长：激素治疗哮喘的潜在、附加机制
2009/03/09
关键词：哮喘；支气管收缩；支气管保护；深呼吸；激素；潮式呼吸
研究发现，呼吸，尤其是深呼吸能够对抗支气管收缩剂刺激引起的气流阻塞。体外用力摇动收缩的气道平滑肌可导致其再伸长，这一现象称作用力摇动诱导的再伸长（force fluctuation-induced relengthening， FFIR）。由于呼吸在肺内对平滑肌有类似于用力摇动的作用，因此FFIR可能是呼吸对抗支气管平滑肌收缩的机制。哮喘时这种支气管保护作用似乎也被损坏，激素治疗可能恢复深呼吸并逆转哮喘患者的支气管收缩。因而激素除了抗炎作用外，还可能通过增强FFIR而对气道平滑肌直接发挥作用。为了证实这一假说，Lakser等测定了犬气管平滑肌束再伸长的程度。
研究结果显示，地塞米松治疗通过增加MAPK磷酸酶-1的表达、抑制p38 MAPK的活性，继而减少p38 MAPK下游靶点——HSP27的磷酸化，从而增强气管平滑肌的FFIR作用。
根据这些研究结果，作者认为，激素可能通过抑制p38MARK活性、增强FFIR而对气道平滑肌发挥直接作用，这可能是激素治疗作用的机制之一。
（韩伟 青岛大学医学院附属青岛市市立医院呼吸科 266071 摘译）
（Eur Respir J 2008; 32:1224-1230）
Eur Respir J 2008; 32:1224-1230
Steroids augment relengthening of contracted airway smooth muscle: potential additional mechanism of benefit in asthma
O. J. Lakser, M. L. Dowell, F. L. Hoyte
Keywords: Asthma, bronchoconstriction, bronchoprotection, deep breaths, steroids, tidal breathing
Breathing (especially deep breathing) antagonises development and persistence of airflow obstruction during bronchoconstrictor stimulation. Force fluctuations imposed on contracted airway smooth muscle (ASM) in vitro result in its relengthening, a phenomenon called force fluctuation-induced relengthening (FFIR). Because breathing imposes similar force fluctuations on contracted ASM within intact lungs, FFIR represents a likely mechanism by which breathing antagonises bronchoconstriction. While this bronchoprotective effect appears to be impaired in asthma, corticosteroid treatment can restore the ability of deep breaths to reverse artificially induced bronchoconstriction in asthmatic subjects. It has previously been demonstrated that FFIR is physiologically regulated through the p38 mitogen-activated protein kinase (MAPK) signalling pathway. While the beneficial effects of corticosteroids have been attributed to suppression of airway inflammation, the current authors hypothesised that alternatively they might exert their action directly on ASM by augmenting FFIR as a result of inhibiting p38 MAPK signalling.
This possibility was tested in the present study by measuring relengthening in contracted canine tracheal smooth muscle (TSM) strips.
The results indicate that dexamethasone treatment significantly augmented FFIR of contracted canine TSM. Canine tracheal ASM cells treated with dexamethasone demonstrated increased MAPK phosphatase-1 expression and decreased p38 MAPK activity, as reflected in reduced phosphorylation of the p38 MAPK downstream target, heat shock protein 27.
These results suggest that corticosteroids may exert part of their therapeutic effect through direct action on airway smooth muscle, by decreasing p38 mitogen-activated protein kinase activity and thus increasing force fluctuation-induced relengthening.
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