Modulative effect of a new hydrazide derivative on wheat-induced pulmonary inflammation in rats.

Abstract

What is the central question of this study? What is the mechanism of wheat-induced pulmonary inflammation and how does a hydrazide derivative modulate it? What is the main finding and its importance? A hydrazide derivative significantly reduced wheat-induced pulmonary inflammation in a rat model mainly by down-regulating inflammatory cell infiltration, pathological lesions in the lungs and the level of pro-inflammatory cytokines, COX-1, COX-2 and T-cell proliferation. We investigated the ameliorative anti-inflammatory effect of a previously synthesized hydrazide derivative (N'-(4-methoxybenzylidene)-6-(4-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carbohydrazide; MD) as an immunomodulator in a newly developed allergen-induced pulmonary inflammation (AIPI) rat model. Wheat and thresher dust were used as allergens to induce pulmonary inflammation while MD was used to reverse the inflammatory response. Blood and bronchoalveolar lavage fluid (BALF) were collected after killing the rats and inflammatory cells were counted. Histological analysis of lung airways was carried out by haematoxylin and eosin and periodic acid-Schiff staining while the level of total serum IgE, interleukin (IL)-4, IL-5 and cyclooxygenase (COX)-1 in BALF and in vitro T-cell proliferation in spleen were measured through enzyme-linked immunosorbent assay. mRNA expression level of IL-4, IL-5, IL-13, transforming growth factor β (TGF-β), interferon-γ, tumour necrosis factor α, COX-1 and COX-2 was evaluated by qRT-PCR. A liver and kidney function test was used to observe any toxic impact of MD. The results indicated that 2mg of wheat and thresher dust led to higher levels of inflammatory cytokines in the blood, BALF and lung airways of rats. MD potentially down-regulated the inflammatory cell infiltration in BALF and pathological lesions in the lung airways of AIPI rats. MD significantly suppressed the elevated total serum IgE, along with IL-4, IL-5, IL-13, TGF-β, COX-1 and COX-2 mRNA expression and T-cell proliferation in spleen. In conclusion, MD at 10mgkg-1 exhibited a significant reduction in all the markers in both wheat- and thresher dust-induced pulmonary inflammation mainly by inhibiting pro-inflammatory cytokine production and T-cell proliferation. The data suggest that inhibition of the T-cell response may be responsible for the modulative effect of MD in an AIPI rat model.