Noveral J P, Grunstein M M
Division of Pulmonary Medicine, Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104, USA.
Am J Physiol. 1995 Sep;269(3 Pt 1):L339-43. doi: 10.1152/ajplung.1995.269.3.L339.
The tachykinins, substance P (SP) and neurokinins A (NKA) and B (NKB), have been identified in the respiratory tract and implicated in mediating neurogenic inflammation of the airways. To the extent that these neuropeptides may be involved in the pathogenesis of asthma, a condition associated with hyperplasia of airway smooth muscle (ASM), we examined the mitogenic effects and mechanisms of action of tachykinins in cultured rabbit ASM cells. SP was found to elicit dose-dependent (10(-14) to 10(-4) M) stimulation of ASM cell proliferation, with a mean (+/- SE) maximal increase in cell number of 169 +/- 6.1% of control. In contrast, NKA and NKB had little and no effect on ASM cell growth, respectively. Because SP is nonselective in its binding to the tachykinin receptors, to identify the specific NK receptor subtype(s) mediating the promitogenic action of SP, in separate studies we found that 1) the NK1-receptor-specific agonist, [beta-Ala4, Sar9, Met(O2)11]SP-(4-11) induced stimulation of ASM cell growth similar in magnitude to that elicited by SP; 2) in contrast, neither the NK1- nor NK2-receptor-specific agonists, [beta-Ala8]NKA-(4-10) and [MePhe7]NKB, respectively, had any effect on ASM cell growth; and 3) the promitogenic action of SP was inhibited by the NK1-receptor antagonist, GR-82,334. Moreover, in extended experiments, we found that the phospholipase C and phospholipase A2 inhibitors, neomycin and quinacrine, respectively, each inhibited SP-induced ASM cell proliferation by approximately 45%. Collectively, these observations provide new evidence that the tachykinin SP induces ASM cell proliferation, and that this action is mediated by transmembrane signaling coupled to selective activation of the NK1 receptor.
速激肽、P物质（SP）、神经激肽A（NKA）和神经激肽B（NKB）已在呼吸道中被鉴定出来，并被认为与介导气道的神经源性炎症有关。鉴于这些神经肽可能参与哮喘的发病机制，而哮喘是一种与气道平滑肌（ASM）增生相关的疾病，我们研究了速激肽在培养的兔ASM细胞中的促有丝分裂作用及其作用机制。发现SP能引起ASM细胞增殖的剂量依赖性（10^(-14)至10^(-4) M）刺激，细胞数量平均（±SE）最大增加为对照的169±6.1%。相比之下，NKA和NKB分别对ASM细胞生长几乎没有影响和没有影响。由于SP与速激肽受体的结合是非选择性的，为了确定介导SP促有丝分裂作用的特定NK受体亚型，在单独的研究中我们发现：1）NK1受体特异性激动剂[β - Ala4，Sar9，Met(O2)11]SP-(4 - 11)诱导的ASM细胞生长刺激程度与SP引起的相似；2）相比之下，NK1和NK2受体特异性激动剂[β - Ala8]NKA-(4 - 10)和[MePhe7]NKB分别对ASM细胞生长均无任何影响；3）SP的促有丝分裂作用被NK1受体拮抗剂GR - 82,334抑制。此外，在进一步的实验中，我们发现磷脂酶C和磷脂酶A2抑制剂新霉素和奎纳克林分别使SP诱导的ASM细胞增殖抑制约45%。总的来说，这些观察结果提供了新的证据，即速激肽SP诱导ASM细胞增殖，并且这种作用是由与NK1受体选择性激活偶联的跨膜信号传导介导的。
