Abstract
Acute lung injury induced by ischemia–reperfusion (I/R)-associated pulmonary inflammation is associated with high rates of morbidity. Despite advances in the clinical management of lung disease, molecular therapeutic options for I/R-associated lung injury are limited. Zinc finger protein 36 (ZFP36) is an AU-rich element-binding protein that is known to suppress the inflammatory response. A ZFP36 binding site occurs in the 3ʹ UTR of the cAMP‐response element-binding protein (CREB) binding protein (CREBBP) gene, which is known to interact with apoptotic proteins to promote apoptosis. In this study, we investigate the involvement of ZFP36 and CREBBP on I/R-induced lung injury in vivo and in vitro. Intestinal ischemia/reperfusion (I/R) activates inflammatory responses, resulting in injury to different organs including the lung. Lung tissues from ZFP36-knockdown mice and mouse lung epithelial (MLE)-2 cells were subjected to either Intestinal I/R or hypoxia/reperfusion, respectively, and then analyzed by Western blotting, immunohistochemistry, and real-time PCR. Silico analyses, pull down and RIP assays were used to analyze the relationship between ZFP36 and CREBBP. ZFP36 deficiency upregulated CREBBP, enhanced I/R-induced lung injury, apoptosis, and inflammation, and increased I/R-induced lung fibrosis. In silico analyses indicated that ZFP36 was a strong negative regulator of CREBBP mRNA stability. Results of pull down and RIP assays confirmed that ZFP36 direct interacted with CREBBP mRNA. Our results indicated that ZFP36 can mediate the level of inflammation-associated lung damage following I/R via interactions with the CREBBP/p53/p21/Bax pathway. The downregulation of ZFP36 increased the level of fibrosis.
Highlights
Acute lung injury, resulting from systemic inflammatory responses as a consequence of ischemia–reperfusion (I/R), has limited therapeutic options and is associated with high morbidity [1, 2].Injury to the lung from I/R can occur through a global response from thoracic surgery to other organs, such as the liver [3], heart [4], kidneys [5], and intestine [6]
Our findings that Zinc finger protein 36 (ZFP36) is upregulated in lung injury derived from intestinal I/R, and suppression of ZFP36 led to increased levels of proinflammatory proteins (IL-1β, tumor necrosis factor (TNF)-α, and IL-6) and severity of lung injury is similar to other studies [31]
We examined the role of ZFP36 in mRNA degradation by assessing its interactions with CREBBP, which promotes apoptosis following I/R and possesses an AU-rich 3ʹUTR ZFP36 binding site
Summary
Acute lung injury, resulting from systemic inflammatory responses as a consequence of ischemia–reperfusion (I/R), has limited therapeutic options and is associated with high morbidity [1, 2].Injury to the lung from I/R can occur through a global response from thoracic surgery to other organs, such as the liver [3], heart [4], kidneys [5], and intestine [6]. Acute lung injury, resulting from systemic inflammatory responses as a consequence of ischemia–reperfusion (I/R), has limited therapeutic options and is associated with high morbidity [1, 2]. The inflammatory process in acute lung injury is wellstudied, less is known about the role played by apoptosis and fibrosis. Drugs that ameliorate the inflammatory processes associated with I/R can reduce levels of fibrosis in the lung and alleviate injury [9]. In conjunction with interleukins (ILs), TNF-α is known to activate the NF-κB and JAK/STAT pathway in response to lung injury to induce the expression of several major chemokines including CXCL13, which is involved in pulmonary fibrosis [18]
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