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Acknowledgments br Introduction Pulmonary fibrosis PF is a
Acknowledgments
Introduction
Pulmonary fibrosis (PF) is a chronic, fibrosing interstitial pneumonia and a crushing disease that occurs as a result of a variety of lung injuries, including auto-immune, tuberculosis and traumatic insult [1], [2]. PF is characterized by the accumulation of extracellular matrix (ECM), a large amount of collagen deposition and production of pro-inflammatory cytokines [3], [4]. The prevalence and incidence of idiopathic pulmonary fibrosis increase with age, and its rate has increased among males in recent years [5]. At present, multiple strategies, including the use of anti-oxidants, glucocorticoids and anti-fibrinolytics, have been shown to be effective in human and animal models of PF [6]. However, convenient and effective methods for prevention and treatment of PF are unavailable. Therefore, it is necessary to explore new possible target or agents to prevent and restrain PF.
Kruppel-like transcription factors (KLF) are zinc finger proteins that are implicated in many biological processes, including the regulation of inflammation, cell proliferation and apoptosis [7]. Kruppel-like factor 2 (KLF2) acts as a member of KLFs, and is involved in the progress of a variety of diseases, including vascular development and disease, Alzheimer's disease and liver fibrosis [8], [9], [10]. Moreover, KLF2, also known as Lung Kruppel-like factor (LKLF), is predominantly expressed in lung tissues, is essential for normal lung development [11], and plays an important role in the regulation of various lung diseases, including pulmonary hypertension [12] and chronic obstructive pulmonary disease [13]. Recently, it has been reported that KLF2 is downregulated in active tuberculosis patients [14], [15], as well as in mln4924 and chronic obstructive pulmonary disease [16]. However, the effects of KLF2 on lung fibrosis remain unclear.
Here we show that KLF2 is up-regulated in bleomycin (BLM)-induced PF. Overexpression of KLF2 blocks lung fibrosis, leading to a reduction in the destruction of alveolar space, pulmonary interstitial collagen hyperplasia, and protein deposition, as well as a decrease in the hydroxyproline content, and the expression of collagen type 1a1 (col1a1), collagen type 3a1 (col3a1), and α-SMA. Adenoviral transduction of KLF2 leads to a decrease of TNF-α, IL-1β, and IL-6 expression in BALF and lung tissues. Also, we show that the col1a1, col3a1 and α-SMA transcript levels are suppressed by KLF2 overexpression in vitro. Also, KLF2 inhibited the expression of c-Jun and c-Fos induced by BLM in rats. Taken together, KLF2 alleviates lung fibrosis, and the inflammatory response may be through regulation of AP-1, providing a new potential strategy and targets for the prevention and treatment of PF.
Materials and methods
Results
Discussion
In this work, we confirmed that KLF2 attenuates lung fibrosis in vivo and in vitro, and inhibits the production of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. The protective effect of KLF2 on lung tissues is associated with a regulation of AP-1.
Seventeen members of the KLF family have been identified in mammalian cells, which are referred to as KLF1-KLF17 [18]. Among these, KLF4 and KLF6 are downregulated in non-small cell lung cancer, inhibit cell growth and induce apoptosis [19], [20]. KLF4 suppresses TGF-β1-induced EMT in lung epithelial cells [21]. KLF2 is connected with the development of multiple lung diseases, and is involved in physiological and pathological processes of the lung. A recent study revealed that KLF2 preserves the lung vascular barrier function [22]. Also, KLF2 expression was downregulated at 12 h post exposure to paraquat and can serve as a molecular marker of early lung injury [23]. Similarly, here we demonstrate that KLF2 is reduced in BLM-induced lung injury, suggesting that KLF2 night be implicated in the progress of lung fibrosis induced by BLM.
Fibrosis is associated with the destruction of normal tissue, epithelial cell damage, fibroblast proliferation, the production of pro-inflammatory cytokines and excessive extracellular matrix deposition. It has been reported that exogenous hepatic KLF2 overexpression alleviates liver fibrosis and endothelial dysfunction in cirrhosis [10]. Moreover, its family members KLF4 and KLF11 also impede cardiac hypertrophy and fibrosis [24], [25]. In BLM-induced lung fibrosis, we found that the destruction of the alveolar space, pulmonary interstitial collagen hyperplasia and protein deposition were improved by KLF2 overexpression. In addition, adenoviral transduction of KLF2 prevented the hydroxyproline content in lung tissue, and downregulated col1a1, col3a1 and α-SMA expression, indicating that KLF2 ameliorates BLM-induced lung fibrosis, suggesting that KLF2 exhibits anti-fibrosis effects in liver and lung tissues.