Kotaro Kumano

Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice

TGF-beta plays an important role in lung fibrosis, which is a major cause of suffering and death seen in pulmonary disease. Smad7 has been recently identified as an antagonist of TGF-beta signaling. To investigate whether this novel molecule can be exploited for therapy of lung fibrosis, we determined the effect of exogenous Smad7, introduced by a recombinant human type 5 adenovirus vector, on bleomycin-induced lung fibrosis in mice. C57BL/6 mice with bleomycin-induced lungs received an intratracheal injection of a recombinant adenovirus carrying mice Smad7 cDNA. These mice demonstrated suppression of type I precollagen mRNA, reduced hydroxyproline content, and no morphological fibrotic responses in the lungs when compared with mice administered adenovirus carrying Smad6 cDNA. In addition, we found that expression of Smad7 transgene blocked Smad2 phosphorylation induced by bleomycin in mouse lungs. These data indicated that gene transfer of Smad7 (but not Smad6) prevented bleomycin-induced lung fibrosis, suggesting that Smad7 may have applicability in the treatment of pulmonary fibrosis.

IgE‐dependent enhancement of Th2 cell‐mediated allergic inflammation in the airways

T helper 2 (Th2) cell‐derived cytokines, including interleukin (IL)‐4, IL‐5 and IL‐13, play important roles in causing allergic airway inflammation. In contrast to Th2 cells, however, the role of IgE and mast cells in inducing allergic airway inflammation is not understood fully. In the present study, we addressed this point using transgenic mice expressing trinitrophenyl (TNP)‐specific IgE (TNP–IgE mice), which enable us to investigate the role of IgE without the influence of antigen‐specific T cell activation and other immunoglobulins. When the corresponding antigen, TNP–BSA, was administered intranasally to TNP–IgE mice, a large number of CD4+ T cells were recruited into the airways. In contrast, TNP–BSA administration did not induce eosinophil recruitment into the airways or airway hyperreactivity. Furthermore, when ovalbumin (OVA)‐specific Th2 cells were transferred to TNP–IgE mice and the mice were challenged with inhaled OVA, TNP–BSA administration increased OVA‐specific T cell recruitment and then enhanced Th2 cell‐mediated eosinophil recruitment into the airways. These results indicate that IgE‐induced mast cell activation principally induces CD4+ T cell recruitment into the airways and thus plays an important role in enhancing Th2 cell‐mediated eosinophilic airway inflammation by recruiting Th2 cells into the site of allergic inflammation.

Role of IgE in Th2 Cell-Mediated Allergic Airway Inflammation

Recent studies with gene knockout mice have demonstrated that T helper 2 (Th2) cell-derived cytokines, including IL-4, IL-5, and IL-13, play important roles in causing allergic airway inflammation. In addition to Th2 cytokines, IgE-dependent activation of mast cells has been suggested to play a role in allergic airway inflammation. In this review, we will discuss the role of IgE in Th2 cell-mediated allergic airway inflammation. We used IgE transgenic mice, which enabled us to investigate the role of IgE without the influence of activated T cells and other immunoglobulins. Whereas IgE cross-linking by antigens did not induce eosinophil recruitment into the airways or airway hyperreactivity, IgE cross-linking induced CD4+ T cell recruitment into the airways. In addition, when antigen-specific Th2 cells were transferred to IgE transgenic mice, IgE cross-linking significantly enhanced antigen-induced eosinophil recruitment into the airways. These findings suggest that IgE-dependent mast cell activation plays an important role in allergic airway inflammation by recruiting Th2 cells into the site of allergic inflammation.

Systemic T Helper 2 Cell Activation Is Not Sufficient for Antigen-Induced Eosinophil Recruitment into the Airways

Background: Airway eosinophilic inflammation is a characteristic feature of asthma. We have previously shown that antigen-induced eosinophil recruitment into the airways of sensitized BALB/c mice is mediated by CD4+ T cells and IL-5. However, the basis for the eosinophil recruitment into the airway are still largely unknown. Methods: To determine the regulatory mechanisms that control the magnitude of antigen-induced eosinophilic inflammation in the airways, we analyzed antigen-induced eosinophil and T cell infiltration into the trachea in several strains of mice, including BALB/c (H-2d), BALB/b (H-2b), C57BL/6 (H-2b), C57BL/10 (H-2b), and B10.D2 (H-2d) mice. In addition, cytokine production from antigen-stimulated splenocytes and the titer of antigen-specific IgE antibody in serum were assessed. Results: Antigen-induced eosinophil recruitment into the trachea in BALB/c mice was more than 20 times as abundant as that in C57BL/6 mice, the latter of which was also mediated by CD4+ T cells. In contrast, systemic Th2 responses, which were evaluated by the titers of antigen-specific IgE antibody in serum and antigen-induced IL-4 and IL-5 production from splenocytes, were similarly observed in BALB/c mice and C57BL/6 mice. In addition, the antigen-induced eosinophil recruitment into the trachea was high in BALB/b mice, like BALB/c mice, but low in B10.D2 mice. Conclusions: Systemic Th2 responses are not sufficient for causing antigen-induced eosinophil recruitment into the airways and an undefined determinant(s) that exists in the BALB background mice rather than the H-2 haplotype is vital for the regulation of antigen-induced eosinophil recruitment into the airways.