Early Plasma Matrix Metalloproteinase Profiles. A Novel Pathway in Pediatric Acute Respiratory Distress Syndrome

Zinter, Matt S; Delucchi, Kevin; Kong, Michele; Orwoll, Benjamin; Spicer, Aaron C.; Lim, Michelle; Alkhouli, Mustafa F.; Ratiu, Anna; McKenzie, Anne V.; McQuillen, Patrick S.; Dvorak, Christopher C.; Calfee, Carolyn S.; Matthay, Michael A.; Sapru, Anil

doi:10.1164/rccm.201804-0678oc

Cited by 35 publications

(45 citation statements)

References 67 publications

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“…Previous research showed that the expression of MMPs was correlated with the progression of ARDS. The enhanced expression of MMPs was related to inflammation-induced endothelial injury and impaired oxygenation in ARDS [ 81 , 82 ]. Another study revealed that MMP inhibitors suppressed MMP expression in plasma and lung tissue, decreased inflammatory mediator release, and attenuated lung inflammatory injury [ 83 , 84 ].…”

Section: Role Of Neutrophils In Ardsmentioning

confidence: 99%

Understanding the role of neutrophils in acute respiratory distress syndrome

et al. 2021

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Acute respiratory distress syndrome (ARDS) is difficult to treat and is associated with a high mortality rate. The most severe form of coronavirus disease 2019 (COVID-19) also leads to life-threatening ARDS. Neutrophil counts are positively correlated with disease severity in ARDS. Neutrophil activation not only plays a significant role in immune defense against infections, but also causes tissue damage and leads to inflammatory diseases. Activated neutrophils rapidly migrate to inflamed lung tissue, releasing toxic granular contents and generating neutrophil extracellular traps. In the last few decades, it has become apparent that neutrophils occupy a central role in ARDS pathology. In this review, we summarize the neutrophil inflammatory responses and their relationships to ARDS. According to the current literature, understanding the function of neutrophils may be helpful in the treatment of ARDS.

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Section: Role Of Neutrophils In Ardsmentioning

confidence: 99%

Understanding the role of neutrophils in acute respiratory distress syndrome

et al. 2021

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“…Pulmonary fibrosis is a well-recognized feature of acute respiratory distress syndrome (ARDS) [1][2][3], and lipopolysaccharide (LPS) is a considerable factor causing sepsisassociated ARDS and pulmonary fibrosis [4][5][6]. However, the related mechanisms are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

Wan

Xie

et al. 2019

Laboratory Investigation

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ARTICLEThy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis Abstract Lipopolysaccharide (LPS)-induced autophagy inhibition in lung fibroblasts is closely associated with the activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-Akt-mTOR) pathway. However, the underlying mechanism remains unknown. In this study, we demonstrated that LPS activated the PI3K-Akt-mTOR pathway and inhibited lung fibroblast autophagy by depleting thymocyte differentiation antigen-1 (Thy-1) and upregulating integrin β3 (Itgb3). Challenge of the human lung fibroblast MRC-5 cell line with LPS resulted in significant upregulation of integrin β3, activation of the PI3K-Akt-mTOR pathway and inhibition of autophagy, which could be abolished by integrin β3 silencing by specific shRNA or treatment with the integrin β3 inhibitor cilengitide. Meanwhile, LPS could inhibit Thy-1 expression accompanied with PI3K-Akt-mTOR pathway activation and lung fibroblast autophagy inhibition; these effects could be prevented by Thy-1 overexpression. Meanwhile, Thy-1 downregulation with Thy-1 shRNA could mimic the effects of LPS, inducing the activation of PI3K-Akt-mTOR pathway and inhibiting lung fibroblast autophagy. Furthermore, protein immunoprecipitation analysis demonstrated that LPS reduced the binding of Thy-1 to integrin β3. Thy-1 downregulation, integrin β3 upregulation and autophagy inhibition were also detected in a mouse model of LPS-induced pulmonary fibrosis, which could be prohibited by intratracheal injection of Thy-1 overexpressing adeno-associated virus (AAV) or intraperitoneal injection of the integrin β3 inhibitor cilengitide. In conclusion, this study demonstrated that Thy-1 depletion and integrin β3 upregulation are involved in LPS-induced pulmonary fibrosis, and may serve as potential therapeutic targets for pulmonary fibrosis.

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“…In this study we propose activation of TREK-1 K + channels as a potentially new therapeutic approach against HALI, since currently no targeted interventions exist that translate into improved patient outcomes. Recent in vitro studies suggest that overexpression of certain microRNAs (miR16, miR21-5) may protect cultured AT2 cells against HO-induced apoptosis [53][54][55] , and multiple biomarker studies have aimed at predicting the risk of HALI in patients 56,57 . In addition, neutralizing therapies against individual cytokines, including IL-6, TNF-α and CCL-2, have yielded variable results at best in improving inflammatory responses [58][59][60][61] .…”

Section: Discussionmentioning

confidence: 99%

K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

Zyrianova

López

Olcese

et al. 2020

Sci Rep

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No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2P2.1 (TREK-1) K+ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca2+ channels (CaV) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa2+ concentrations. In addition, CCL-2 secretion was decreased after L-type CaV inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.

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Early Plasma Matrix Metalloproteinase Profiles. A Novel Pathway in Pediatric Acute Respiratory Distress Syndrome

Abstract: Pediatric ARDS patients have specific plasma MMP profiles associated with inflammation, endothelial injury, morbidity, and mortality. MMPs may play a role in the pathobiology of children with ARDS.

Cited by 35 publications

References 67 publications

Understanding the role of neutrophils in acute respiratory distress syndrome

Understanding the role of neutrophils in acute respiratory distress syndrome

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

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