[Role of c-Jun N-terminal kinase signal transduction pathway in the course of airway remodeling of asthma rat].

Objective: To study the role of c-Jun N-terminal kinase (JNK) signal transduction pathway in the course of asthma airway remodeling, to explore whether IL-1beta participates in asthma airway remodeling mediated by JNK signal transduction pathway.
Methods: Totally 72 male Sprague-Dawlay rats (6 - 8 weeks old, weighing about 120 g) were randomly divided into control groups (36 rats) and asthma groups (36 rats). The rats were sensitized for inducing asthma by intraperitoneal injection of ovalbumin and AL(OH)3 and were repeatedly exposed to aerosolized ovalbumin for 4, 8, 12 weeks (A4, A8, or A12 group), each had 12 rats, and correspondingly control rats were intraperitoneally injected with 0.9% NaCl, then were repeatedly exposed to 0.9% NaCl for 4, 8, 12 weeks (C4, C8, or C12 group), each had 12 rats. The ultrastructural changes of pulmonary tissues were observed by transmission electron microscope (TEM). The total bronchial wall thickness (Wat) and the airway smooth muscle thickness (Wam) were measured by an image analysis system. The concentrations of IL-1beta in serum and bronchoalveolar lavage fluid (BALF) were tested by a "sandwich" ELISA. The protein expressions of P-JNK and P-c-Jun were detected by immunohistochemical technique. Lung tissue extracts were analyzed for phosphorylation of JNK by Western blotting. Linear correlation analysis showed the correlation between Wat and P-JNK protein, Wam and P-JNK protein, levels of IL-1beta in serum and P-JNK protein, levels of IL-1beta in BALF and P-JNK protein.
Results: In asthma groups, TEM showed alveolar septal proliferation and alveolus type II epithelial cells swelling. Wat and Wam in all asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), and compared with group A4 and group A8, Wat and Wam of group A12 significantly increased (P < 0.01). The concentrations of IL-1beta in serum and BALF of asthma groups were all significantly higher than those of the corresponding control groups (P < 0.01, respectively), and compared with group A4 and group A8, the concentrations of IL-1beta in BALF of group A12 significantly increased (P < 0.01 or P < 0.05), but the levels of IL-1beta in serum were not significantly different among them (P > 0.05). Mean absorbance values (by immunohistochemistry) of P-JNK and P-c-Jun in asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), and compared with group A4 and group A8, those of group A12 significantly increased (P < 0.01 or P < 0.05). The absorbance (by Western Blot) of P-JNK in A4, A8, A12 group was significantly higher than that in C4, C8, C12 groups (P < 0.01, respectively), and compared with group A4, that of P-JNK of A12 significantly increased (P < 0.01), and compared with group A8, there was no significant difference (P > 0.05). Strong positive correlations were found between Wat or Wam and P-JNK (r = 0.823 and r = 0.818, P < 0.01, respectively, n = 68) and between P-JNK and concentration of IL-1beta in serum or BALF (r = 0.717 and r = 0.803, P < 0.01, respectively, n = 68).
Conclusions: The expression of P-JNK and its downstream P-c-Jun in rats of asthma airway remodeling is increased, which implicates that JNK signal transduction pathway plays an important role in the course of asthma airway remodeling. IL-1beta participates in asthma airway remodeling possibly partly through activating JNK signal transduction pathway.