The pathogenesis of asthma remains unclear. An in vivo murine model of antigen-induced airway hyperreactivity and inflammation was developed to investigate the possibility, suggested by a wealth of descriptive human data, that alterations in immunoregulation are important in the genesis of airway hyperreactivity. A/J mice developed airway hyperreactivity and markedly increased numbers of pulmonary inflammatory cells following intraperitoneal sensitization and intratracheal challenge with sheep red blood cells. Notably, eosinophils were a prominent component of the inflammatory infiltrate. The dependence of these phenomena, both pathologic and functional, on CD4+ T lymphocytes was investigated by in vivo depletion of CD4+ cells using the anti-CD4 mAb GK1.5. When administered before antigen challenge, GK1.5 completely prevented both airway hyperreactivity and the infiltration of eosinophils. This model provides the first direct demonstration of the dependence of airway hyperreactivity upon CD4+ T lymphocytes, and the results are consistent with the possibility that eosinophils are effectors of this response.

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Sonic Hedgehog (Shh) plays an essential role in vertebrate organogenesis as well as the development of some cancers, including breast cancer. The aim of the present study was to characterize more precisely its role in breast carcinogenesis and elucidate its regulation mechanisms. The expression of Shh was investigated in 97 breast carcinomas and 22 paired non-tumorous tissues (distant from the primary tumor) by immunohistochemistry and in four breast cell lines by Western blotting. We also analyzed the methylation status of the Shh gene with methylation-specific PCR and assessed whether nuclear factor-kappa B (NF-jB) and Gli1 were expressed in breast tissues by immunohistochemistry. Our results showed that Shh protein expression in breast carcinomas was significant higher than that in normal breast tissues (P < 0.01). The upregulation of Shh in breast carcinomas was correlated significantly with early clinical stage (P < 0.05). In addition, we found a substantial increase in Shh expression at both the mRNA and protein levels in several human breast carcinoma cell lines. The expression level of nuclear Gli1 was positively associated with the expression level of Shh in breast tissues (P < 0.001). Promoter region hypomethylation (43/61, 70.5%) was frequently observed in breast carcinomas and significantly associated with Shh up-regulation (P < 0.05). The DNA methyltransferase inhibitor 5-azacytidine (5-Aza) reduced the methylation of Shh promoter and increased the expression of Shh protein in MDA-MB-435 and MCF-10A cells. Furthermore, most of the breast carcinoma cases with Shh up-regulation had increased expression of NF-jB (35/49, 71.4%; P < 0.001). Taken together, these observations suggest that Shh overexpression is a critical event in breast carcinogenesis, and Shh promoter hypomethylation and NF-jB up-regulation are responsible for the up-regulation of Shh. (Cancer Sci 2010; 101: 927-933)