Effect Of Low Dose Theophylline On Airway Remodeling

Objective:To investigate the effect of low dose theophylline on airway remolding in rat model induced by inhaling acrolein and explores its mechanism. Methods:The Sprague-Dawley (SD) rats were randomly assigned into 4 groups (n=10, respectively):A.control group (inhaled 0.9% normal saline (NS) for 3 hours, twice every day); B.model group (stimulated with 4ppm acrolein for 3 hours, twice every day); C.low dose theophylline intervention group (inhaled acrolein and interaperitoneal injection with theohylline of 4mg/kg/day). D.therapy dose theophylline (10～20μg/ml in Plasma) intervention group(inhaled acrolein and interaperitoneal injection with theohylline of 8mg/kg/day). Lung tissues were acquired after the rats were sacrificed on the 28th day. Theophylline concentration in blood was examined with High Performance Liquid Chromatography; The liveness of epidermal growth factor in lung lavage fluid was examined with E1ASA. TGF-β1 contents were detected by immunohistochemisy, the relative amount of TGF-β1 was analyzed after image grabbing. Nuclear factor-KB was tested with immunohistochemisy. the percentage of transfected cells was analysised after image acquisition;The expression of matrix metalloproteinase 2(MMP2) in lung tissue was observed with immunohistochemisy.The ratio in preleases was analyzed after image grabbing. Results:The plasma theophylline concentrations were respectively 7.12±0.33mg/L in low dose theophylline intervention group and 13.74±0.47mg/L in therapy dose theophylline intervention group.①EGF concentration in BALF:A group (1.27±0.16) ng/ml,B group (1.99±0.14) ng/ml,C group (1.75±0.12) ng/ml,D group (1.67±0.07) ng/ml.Compared with B, concentrations of EGF of A,C,D group decreased, it has significant difference (n=10,P<0.05); Compared with A, concentrations of EGF in C,D groups were increased, it has significant difference (P<0.05), C,D no significant difference between the two groups (P> 0.05).②Expression of TGF-β1in lung airway:The gray value of TGF-β1 in every group is:A group 105.42±10.31,B group 165.58±13.91,C group 129.64±9.68,D group 126.83±6.63. Compared with B,the gray value of TGF-β1 in A,C,D group decreased,it has significant difference (n=10,P<0.05); Compared with A, the gray value of C,D groups were increased, it has significant difference (P <0.05), C,D no significant difference between the two groups (P> 0.05).③Expression of MMP2 in lung airway:A group 29.64±7.49,B group 111.08±9.73,C group 51.45±8.76,D group 49.03±5.48. Compared with B, expression of MMP2 in A,C,D group decreased, it has significant difference (n=10,P<0.05); Compared with A, expression of MMP2 in C,D groups increased, it has significant difference (P<0.05), C,D no significant difference between the two groups (P> 0.05).④Expression of NF-κBp65 in lung airway:The entry of nuclear NF-KBp65 rate in every group is:A group (5.85±1.23)%,B group (35.65±4.89)%,C group (12.70±1.55)%,D group (11.25±1.62)%.Compared with B, The entry of nuclear NF-κBp65 rate in A, C,D group decreased, it has significant difference(n=10,P<0.05); Eompared with A, The entry of nuclear NF-KBp65 in C,D groups increased, it has significant difference (P<0.05), C,D no significant difference between the two groups (P>0.05). Conclusion:Acrolein pulverization could increase The liveness of epidermal growth factor(EGF) in lung lavage fluid of the rats, and it also increased TGF-β1 contents of epithelial cell on airway and the contents of matrix metalloproteinase 2(MMP2)in lung tissue. Meanwhile, it stimulated transfer of NF-κB. After intervened by low dose and therapy dose theophylline, all above-mentioned were obviously reduced. The low dose and therapy dose of theophylline between the two groups not significantly different between the intervention.The results suggested that low dose theophylline and therapy dose theophylline can suppress airway remolding that including irregular airway epithelial repair, smooth muscle hypertrophy, extracellular matrix degradation and so on,caused by acrolein, which was likely related to the suppression of activation of NF-κB.