Abstract
In this study, the bleomycin model of pulmonary fibrosis was utilized to investigate putative anti-fibrotic activity of Ac-SDKP in vivo. Male CD-1 mice received intra-tracheal bleomycin (BLEO, 1 mg/kg) instillation in the absence or presence of Ac-SDKP (a dose of 0.6 mg/kg delivered intra-peritoneally on the day of BLEO treatment, d0, followed by bi-weekly additional doses). To evaluate therapeutic effects in a subset of mice, Ac-SDKP was administered one week after BLEO instillation (d7). Animals were sacrificed at one, two, or three weeks later. Measurement of fluid and collagen content in the lung, Broncho Alveolar Lavage Fluid (BALF) analysis, lung histology, immunohistochemistry (IHC), and molecular analysis were performed. Compared to BLEO-treated mice, animals that received also Ac-SDKP (at both d0 and d7) had significantly decreased mortality, weight loss, inflammation (edema, and leukocyte lung infiltration), lung damage (histological evidence of lung injury), and fibrosis (collagen histological staining and soluble collagen content in the lung) at up to 21 days. Moreover, IHC and quantitative RT-PCR results demonstrated a significant decrease in BLEO-induced IL-17 and TGF-β expression in lung tissue. Importantly, α-SMA expression, the hallmark of myofibroblast differentiation, was also decreased. This is the first report showing not only a preventive protective role of Ac-SDKP but also its significant therapeutic effects in the bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder with poor prognosis similar to lung cancer
In the current study we utilized the identical mouse model of the previous research to investigate in vivo the effects of exogenous Ac-SDKP by comparison with Tβ4, Here we demonstrated that, besides protective effects on mortality, body weight loss and inflammation, Ac-SDKP carried out both preventive and therapeutic actions against lung damage and fibrosis at up to 21 days, as determined by histological score and collagen content in the lung
These findings are in line with our previous observations in vitro and reinforce the anti-fibrotic function of Tβ4 amino-terminal active site containing the four amino acids Ac-SDKP, which can be released from the parent molecule via processing and/ or degradation of intact Tβ4 [18]
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder with poor prognosis similar to lung cancer. Very few pharmacological options are available, and the median survival time is only 3–5 years following diagnosis. The etiology of this fibrotic lung disease is by definition unknown but an understanding of IPF pathophysiology over the last two decades has shifted from a chronic inflammatory process to an abnormal wound healing cascade with aberrant fibroblast/myofibroblast proliferation and accumulation of extracellular matrix (ECM) proteins such as collagen [1, 2]. Consistent antifibrotic effects of Ac-SDKP have been shown in experimental liver [6,7] and kidney fibrosis [8,9]; Ac-SDKP inhibits pulmonary fibrosis in rats with SiO2-induced silicosis [10, 11]
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