Toda Masao, Tulic Meri K, Levitt Roy C, Hamid Qutayba
Meakins-Christie Laboratories, Montreal, Quebec, Canada.
J Allergy Clin Immunol. 2002 Feb;109(2):246-50. doi: 10.1067/mai.2002.121555.
One of the cardinal features of airway remodeling in asthma is mucus gland hyperplasia and mucus overproduction and hypersecretion. Recently, a calcium-activated chloride channel, HCLCA1, was described that is upregulated by IL-9 and thought to regulate the expression of soluble gel-forming mucins, such as MUC5A/C, a critical component of mucus in the airways.
We sought to examine the expression of HCLCA1 in bronchial biopsy specimens of asthmatic subjects compared with those of control subjects and to demonstrate its relationship with IL-9, IL-9 receptor (IL-9R), and markers of mucus production.
Bronchial biopsy specimens from asthmatic (n = 9) and control (n = 10) subjects were stained with periodic acid-Schiff to identify mucus glycoconjugates. IL-9- and IL-9R-positive cells were identified with immunocytochemistry, and HCLCA1 expression was detected by means of in situ hybridization with cRNA probes.
We demonstrate significant increases in IL-9 (P <.001) and IL-9R (P <.05) immunoreactivity, as well as increased expression of HCLCA1 mRNA (P <.001), in the epithelium of asthmatic patients compared with that found in control subjects. There was also an increase in the number of mucusproducing cells in biopsy specimens from asthmatic subjects (P <.001). HCLCA1 mRNA was strongly and selectively colocalized with periodic acid-Schiff and IL-9R-positive epithelial cells. In particular, a strong positive correlation was observed between HCLCA1 mRNA expression and IL-9-positive (r = 0.69, P < 0.01) or IL9R-positive (r = 0.79, P <.01) cells.
An upregulation of HCLCA1 in the IL-9- responsive mucus-producing epithelium of asthmatic subjects compared with that seen in control subjects supports the hypothesis that this channel may be responsible, in part, for the overproduction of mucus in asthmatic subjects. These preliminary findings suggest the inhibition of HCLCA1 may be an important new therapeutic approach to control mucus overproduction in chronic airway disorders.
哮喘气道重塑的主要特征之一是黏液腺增生以及黏液过度产生和分泌。最近，一种钙激活氯离子通道HCLCA1被发现，它受白细胞介素-9（IL-9）上调，并且被认为可调节可溶性凝胶形成黏蛋白的表达，如MUC5A/C，这是气道黏液的关键成分。
我们试图检测哮喘患者支气管活检标本中HCLCA1的表达，并与对照受试者进行比较，同时证明其与IL-9、IL-9受体（IL-9R）以及黏液产生标志物的关系。
对哮喘患者（n = 9）和对照受试者（n = 10）的支气管活检标本进行过碘酸希夫染色以鉴定黏液糖缀合物。通过免疫细胞化学鉴定IL-9和IL-9R阳性细胞，并用cRNA探针原位杂交检测HCLCA1的表达。
与对照受试者相比，我们发现哮喘患者上皮细胞中IL-9（P <.001）和IL-9R（P <.05）的免疫反应性显著增加，同时HCLCA1 mRNA的表达也增加（P <.001）。哮喘患者活检标本中产生黏液的细胞数量也有所增加（P <.001）。HCLCA1 mRNA与过碘酸希夫阳性和IL-9R阳性上皮细胞强烈且选择性地共定位。特别是，在HCLCA1 mRNA表达与IL-9阳性（r = 0.69，P <.01）或IL-9R阳性（r = 0.79，P <.01）细胞之间观察到强正相关。
与对照受试者相比，哮喘患者IL-9反应性黏液产生上皮细胞中HCLCA1上调，支持了该通道可能部分导致哮喘患者黏液过度产生的假说。这些初步发现表明，抑制HCLCA1可能是控制慢性气道疾病中黏液过度产生的一种重要新治疗方法
