LTB4 and montelukast in transplantation-related bronchiolitis obliterans in rats

Lung transplantation is the only effective treatment for end-stage lung diseases. Bronchiolitis obliterans, which is known as non-infectious chronic lung allograft dysfunction (CLAD) in the new classification, is the greatest threat to long-term survival after lung transplantation. This study investigated the role of leukotriene B4 (LTB4) and montelukast in transplantation-related bronchiolitis obliterans and discussed the pathophysiological significance of LTB4 in chronic rejection.

Rats were randomly divided into an experimental group (montelukast), a positive control group (dexamethasone), and a blank control group (normal saline solution; NS). Each piece of trachea removed from a F344 rat was transplanted into a Lewis rat through a 5-mm incision at the episternum by subcutaneous embedding. The recipients were treated with gastric lavage with 3 mg/kg · d montelukast suspension, 1 mg/kg · d dexamethasone, and 1 mL/kg · d NS, respectively, in each group. On Day 28, peripheral blood was drawn to measure the white blood cell counts and plasma LTB4 levels. The donor specimens were stained by H-E and Masson, and their organizational structure and extent of fibrosis were visually assessed. The measurement data were compared using one-way analysis of variance, and the categorical data were compared using the chi-square test. A P value of less than 0.05 was considered to indicate statistical significance.

The white blood cell counts of the montelukast, dexamethasone, and NS groups were (16.0 ± 4.2) × 10⁹/L, (19.5 ± 11.6) × 10⁹/L, and (25.8 ± 3.6) × 10⁹/L; no statistical significance was found (P = 0.101). The concentrations of LTB4 were 2230 ± 592 pg/mL, 1961 ± 922 pg/mL, and 3764 ± 1169 pg/mL, and statistical significance was found between the NS group and each of the others (P = 0.009). The percentages of tracheal occlusion were 73.6% ± 13.8%, 23.4% ± 3.2%, and 89.9% ± 11.3%, and statistical significance was found among the three groups (P = 0.000).

The study established a model to simulate bronchiolitis obliterans after clinical lung transplantation. Oral administration of montelukast reduced plasma LTB4 levels in rats and played a preventive role against tracheal fibrosis after transplantation. This suggests that LTB4 may be involved in bronchiolitis obliterans after pulmonary transplantation. This study indicates a new direction for research into the prevention and treatment of bronchiolitis obliterans after lung transplantation.