Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced lung injury

Liu, Dejie; Yan, Zhibo; Minshall, Richard D.; Schwartz, David E.; Chen, Yuguo; Hu, Guochang

doi:10.1152/ajplung.00349.2011

Cited by 33 publications

(47 citation statements)

References 44 publications

(69 reference statements)

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“…A well-established in vivo mouse model of VILI was utilized as described previously (12,19,40). Briefly, mice were anesthetized with an intraperitoneal injection of a ketamine/xylazine mixture (75 mg/kg) and inhalation of 1% isoflurane for maintenance.…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…Western blot analysis of lysates of mouse resident alveolar macrophages and lung homogenates was performed as previously described (19,36,40). Briefly, fresh lung tissues were lysed on ice in the buffer containing 1 mM PMSF, 0.2 U/ml aprotinin, and 1 mM sodium orthovanadate.…”

Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

“…Protein concentration in BAL was determined with bicinchoninic acid method as an index of increased permeability of the alveolarcapillary barriers (12,19,38). Extravascular lung water (ELW) was used as an index of lung water content and edema (19).…”

Section: Assessment Of Pulmonary Vascular Permeability and Edema Formmentioning

confidence: 99%

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Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation

Zhang

Liu

Dull

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 307: L173-L185, 2014. First published May 16, 2014 doi:10.1152/ajplung.00083.2014.-The inflammatory response is a primary mechanism in the pathogenesis of ventilator-induced lung injury. Autophagy is an essential, homeostatic process by which cells break down their own components. We explored the role of autophagy in the mechanisms of mechanical ventilation-induced lung inflammatory injury. Mice were subjected to low (7 ml/kg) or high (28 ml/kg) tidal volume ventilation for 2 h. Bone marrow-derived macrophages transfected with a scrambled or autophagy-related protein 5 small interfering RNA were administered to alveolar macrophage-depleted mice via a jugular venous cannula 30 min before the start of the ventilation protocol. In some experiments, mice were ventilated in the absence and presence of autophagy inhibitors 3-methyladenine (15 mg/kg ip) or trichostatin A (1 mg/kg ip). Mechanical ventilation with a high tidal volume caused rapid (within minutes) activation of autophagy in the lung. Conventional transmission electron microscopic examination of lung sections showed that mechanical ventilation-induced autophagy activation mainly occurred in lung macrophages. Autophagy activation in the lungs during mechanical ventilation was dramatically attenuated in alveolar macrophage-depleted mice. Selective silencing of autophagyrelated protein 5 in lung macrophages abolished mechanical ventilation-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and lung inflammatory injury. Pharmacological inhibition of autophagy also significantly attenuated the inflammatory responses caused by lung hyperinflation. The activation of autophagy in macrophages mediates early lung inflammation during mechanical ventilation via NLRP3 inflammasome signaling. Inhibition of autophagy activation in lung macrophages may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury. lung injury; autophagy; mechanical ventilation; inflammasome; macrophage MECHANICAL VENTILATION not only saves the lives of patients with respiratory failure but also initiates and exacerbates lung injury known as ventilator-induced lung injury (VILI), which in turn contributes to patient morbidity and mortality (11). VILI is characterized by an influx of inflammatory cells, increased pulmonary vascular permeability, and endothelial and epithelial cell death. The release of proinflammatory cytokines by lung cells in response to mechanical stretch is a crucial event for initiation and/or potentiation of VILI and may cause systemic inflammatory response and multiple system organ failure (4,22,35). The alveolar macrophages (AMs) (5, 7, 26), neutrophils (42), alveolar epithelium (35), and endothelium (10) are all involved in the production of proinflammatory cytokines during mechanical ...

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Section: Experimental Protocolsmentioning

confidence: 99%

Section: Western Blotting and Immunoprecipitationmentioning

confidence: 99%

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Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation

Zhang

Liu

Dull

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In a ventilator-induced lung injury model, calpain inhibitors, or gene silencing, led to reduce neutrophil infiltration and edema [51]. In endotoxemia models, calpain activation also leads to damage of cardiac, lung, and muscle tissues in mice [29,30,52].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, calpain inhibitors were shown to block IL-1α processing and release downstream of activators of the inflammasome, and IL-1α was required for neutrophil recruitment to the peritoneum in a sterile inflammation model [25]. Although release of both p33 and p17 were detected during sterile inflammation, the exact contributions of these cytokines to IL-1R1 signaling was not reported [25] [51]. In endotoxemia models, calpain activation also leads to damage of cardiac, lung, and muscle tissues in mice [29,30,52].…”

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Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model

et al. 2013

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Activation of the innate immune system is critical for clearance of bacterial pathogens to limit systemic infections and host tissue damage. Here, we report a key role for calpain proteases in bacterial clearance in mice with acute peritonitis. Using transgenic mice expressing Cre recombinase primarily in innate immune cells (fes-Cre), we generated conditional capns1 knockout mice. Consistent with capns1 being essential for stability and function of the ubiquitous calpains (calpain-1, calpain-2), peritoneal cells from these mice had reduced levels of calpain-2/capns1, and reduced proteolysis of their substrate selenoprotein K. Using an acute bacterial peritonitis model, we observed impaired bacterial killing within the peritoneum and development of bacteremia in calpain knockout mice. These defects correlated with significant reductions in IL-1α release, neutrophil recruitment, and generation of reactive oxygen species in calpain knockout mice with acute bacterial peritonitis. Peritoneal macrophages from calpain knockout mice infected with enterobacteria ex vivo, were competent in phagocytosis of bacteria, but showed impaired clearance of intracellular bacteria compared with control macrophages. Together, these results implicate calpains as key mediators of effective innate immune responses to acute bacterial infections, to prevent systemic dissemination of bacteria that can lead to sepsis. Keywords: Bacterial infection r Calpains r Neutrophils r Phagocytosis r Reactive oxygen speciesAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionBacterial infection triggers pattern-recognition receptor (PRR) signaling within host cells designed to allow rapid bacterial clearance and avoid progression to systemic infection [1]. In bacterial Correspondence: Dr. Andrew W. B. Craig e-mail: andrew.craig@queensu.ca peritonitis, resident innate immune cells in the peritoneum (e.g. mast cells, macrophages) orchestrate the immune response via rapid release of preformed and de novo generated vasoactive mediators, cytokines, and chemokines [2][3][4]. This leads to recruitment of neutrophils and bacterial capture in neutrophil extracellular traps [5]. Bacterial clearance is facilitated by rapid degranulation, production of ROS and reactive nitrogen species, and phagocytosis by neutrophils and macrophages [6]. Balancing this potent immune response is critical to eliminate the pathogens prior to systemic dissemination and avoid tissue damage observed C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 832Vijay Kumar et al. Eur. J. Immunol. 2014. 44: 831-841 in severe sepsis [3]. Failure to tightly control production of proinflammatory cytokines such as IL-1, are also linked to the development of autoinflammatory disorders [7]. Thus, a better understanding of positive and negative regulation of PRR signaling may inform the development of more effective treatments for these diseases. Calpains are intracellular, calcium (Ca ++ )-dependent cysteine...

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Expression profiling analysis of long noncoding RNAs in a mouse model of ventilator‐induced lung injury indicating potential roles in inflammation

Zhang

Wang

et al. 2019

J of Cellular Biochemistry

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The key regulators of inflammation underlying ventilator-induced lung injury (VILI) remain poorly defined. Long noncoding RNAs (lncRNAs) have been implicated in the inflammatory response of many diseases; however, their roles in VILI remain unclear. We, therefore, performed transcriptome profiling of lncRNA and messenger RNA (mRNA) using RNA sequencing in lungs collected from mice model of VILI and control groups. Gene expression was analyzed through RNA sequencing and quantitative reverse transctiption polymerase chain reaction. A comprehensive bioinformatics analysis was used to characterize the expression profiles and relevant biological functions and for multiple comparisons among the controls and the injury models at different time points. Finally, lncRNA-mRNA coexpression networks were constructed and dysregulated lncRNAs were analyzed functionally. The mRNA transcript profiling, coexpression network analysis, and functional analysis of altered lncRNAs indicated enrichment in the regulation of immune system/inflammation processes, response to stress, and inflammatory pathways. We identified the lncRNA Gm43181 might be related to lung damage and neutrophil activation via chemokine receptor chemokine (C-X-C) receptor 2. In summary, our study provides an identification of aberrant lncRNA alterations involved in inflammation upon VILI, and lncRNA-mediated regulatory patterns may contribute to VILI inflammation. K E Y W O R D Sinflammation, long noncoding RNA, RNA sequencing, ventilator-induced lung injury

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Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced lung injury

Cited by 33 publications

References 44 publications

Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation

Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation

Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model

Expression profiling analysis of long noncoding RNAs in a mouse model of ventilator‐induced lung injury indicating potential roles in inflammation

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