It has been demonstrated that the

It has been demonstrated that the hallmarks of pulmonary fibrosis are a loss of endothelial function and subsequent activation of the immune system, which is considered as a direct outcome affected by intracellular pro-inflammatory responses [26]. Thus, inhibition of early inflammation could be an intriguing alternative approach for blocking the formation of pulmonary fibrosis. Increasing evidence demonstrates that pro-inflammatory cytokines TNF-α, IL-1β and IL-6 promote the development of lung fibrosis [27], [28]. In our current study, we show that KLF2 notably blocks the BLM-induced production of the pro-fibrotic cytokines release TNF-α, IL-1β and IL-6 in both BALF and lung tissues, indicating that KLF2 has a strong property to inhibit inflammatory mediators that alleviate BLM-induced inflammatory injury. According to our study, the anti-fibrotic effect of KLF2 in the BLM-treated rats is related to the amelioration of BLM-induced inflammatory response and extracellular matrix protein deposition. TGF-β1 is considered the major pro-fibrotic cytokine, and numerous studies support its central role in a variety of fibrotic diseases [29]. It has been shown that TGF-β1 is the most important factor for inducing the activation and differentiation of fibroblasts in the BLM-induced pulmonary fibrosis model [30]. Multiple lines of evidence have indicated that TGF-β1 stimulates collagen synthesis and extracellular matrix deposition [31], [32]. Therefore, we investigated the role of KLF2 in mediating TGF-β1-induced pulmonary fibrosis, and we demonstrate that KLF2 attenuates TGF-β1-mediated pulmonary fibrosis in vivo. Given its anti-inflammatory and anti-fibrotic actions enhancing KLF2 jak stat pathway seems a viable therapeutic option. We further investigated the underlying mechanism of KLF2 in BLM-induced lung fibrosis. It has been reported that KLF2 inhibits AP-1 activity and promoter response [33]. The transcription factor AP-1 is a heterodimeric molecule composed of members of the Jun (c-Jun, JunB and JunD) and Fos (c-Fos, FosB, Fra-1 and Fra-2) families [34]. A previous study also indicated that the selective AP-1 inhibitor, T-5224, selectively reduces collagen synthesis in systemic sclerosis fibroblasts and effectively prevents the development of experimental dermal fibrosis [35]. Additionally, AP-1 has been reported as an interesting candidate for anti-fibrotic therapy [36]. In our current study, we demonstrate the involvement of KLF2 in the pathogenesis of pulmonary fibrosis in vitro and in vivo potentially by inhibiting AP-1.
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Acknowledgements
Introduction In patients with Marfan syndrome (MFS), dilatation of the aortic root due to fibrillin fragmentation and deficiency of the aortic wall necessitates cardiovascular surgery in most patients. Aortic valve–sparing re-implantation technique represents a relatively safe method with favorable long-term results that avoids the need for lifelong anticoagulation. Recently, using the selective AT1 receptor blocker losartan attenuating the canonical transforming growth factor-β (TGF-β) signaling in the aorta, an abrogated aneurysm progression in mice was demonstrated. However, recent clinical studies denied a protective effect of sartans in Marfan patients. Therefore, an effective medical therapy that reliably prevents the development of the vascular phenotype with aortic root aneurysm in MFS is still not available. It has been shown that high expression and activity of matrix metalloproteinases (MMPs) in aortic smooth muscle cells (AoSMC) lead to medial elastolysis in patients with infrarenal aneurysms (AAA) or MFS by destruction of structural matrix molecules. Recent studies demonstrated upregulation of elastolytic MMP activity in these patients and in a murine model of MFS, especially MMP-2 and MMP-9. Inhibition of MMP activity with doxycycline or losartan has been shown to reduce aortic dilatation.