Tunicamycin Protects against LPS-Induced Lung Injury

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Abstract

The pulmonary endothelium is a dynamic semipermeable barrier that orchestrates tissue-fluid homeostasis; regulating physiological and immunological responses. Endothelial abnormalities are caused by inflammatory stimuli interacting with intracellular messengers to remodel cytoskeletal junctions and adhesion proteins. Those phenomena are associated with sepsis, acute lung injury, and acute respiratory distress syndrome. The molecular processes beyond those responses are the main interest of our group. Unfolded protein response (UPR) is a highly conserved molecular pathway resolving protein-folding defects to counteract cellular threats. An emerging body of evidence suggests that UPR is a promising target against lung and cardiovascular disease. In the present study, we reveal that Tunicamycin (TM) (UPR inducer) protects against lipopolysaccharide (LPS)-induced injury. The barrier function of the inflamed endothelium was evaluated in vitro (transendothelial and paracellular permeability); as well as in mice exposed to TM after LPS. Our study demonstrates that TM supports vascular barrier function by modulating actomyosin remodeling. Moreover, it reduces the internalization of vascular endothelial cadherin (VE-cadherin), enhancing endothelial integrity. We suggest that UPR activation may deliver novel therapeutic opportunities in diseases related to endothelial dysregulation.

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Acute respiratory distress syndrome

Michael Matthay, Rachel L. Zemans, Guy Zimmerman … (2019)

The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30–40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.

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TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages.

Fabio Martinon, Xi Chen, Ann-Hwee Lee … (2010)

Sensors of pathogens, such as Toll-like receptors (TLRs), detect microbes to activate transcriptional programs that orchestrate adaptive responses to specific insults. Here we report that TLR4 and TLR2 specifically activated the endoplasmic reticulum (ER) stress sensor kinase IRE1alpha and its downstream target, the transcription factor XBP1. Previously described ER-stress target genes of XBP1 were not induced by TLR signaling. Instead, TLR-activated XBP1 was required for optimal and sustained production of proinflammatory cytokines in macrophages. Consistent with that finding, activation of IRE1alpha by ER stress acted in synergy with TLR activation for cytokine production. Moreover, XBP1 deficiency resulted in a much greater bacterial burden in mice infected with the TLR2-activating human intracellular pathogen Francisella tularensis. Our findings identify an unsuspected critical function for XBP1 in mammalian host defenses.

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Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization.

N Yang, O Higuchi, K Ohashi … (1998)

Rac is a small GTPase of the Rho family that mediates stimulus-induced actin cytoskeletal reorganization to generate lamellipodia. Little is known about the signalling pathways that link Rac activation to changes in actin filament dynamics. Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3; however, the kinases responsible for this phosphorylation have not been identified. Here we show that LIM-kinase 1 (LIMK-1), a serine/threonine kinase containing LIM and PDZ domains, phosphorylates cofilin at Ser 3, both in vitro and in vivo. When expressed in cultured cells, LIMK-1 induces actin reorganization and reverses cofilin-induced actin depolymerization. Expression of an inactive form of LIMK-1 suppresses lamellipodium formation induced by Rac or insulin. Furthermore, insulin and an active form of Rac increase the activity of LIMK-1. Taken together, our results indicate that LIMK-1 participates in Rac-mediated actin cytoskeletal reorganization, probably by phosphorylating cofilin.