IL-1β suppression of VE-cadherin transcription underlies sepsis-induced inflammatory lung injury

Xiong, Shiqin; Hong, Zhigang; Huang, Long Shuang; Tsukasaki, Yoshikazu; Nepal, Saroj; Di, Anke; Zhong, Ming; Wu, Wei; Ye, Zhiming; Gao, Xiaopei; Rao, Gadiparthi N.; Mehta, Dolly; Rehman, Jalees; Malik, Asrar B.

doi:10.1172/jci136908

Cited by 127 publications

(104 citation statements)

References 55 publications

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“…This finding links a cytokine storm directly to capillary leak, and aggravation of the adult respiratory syndrome (ARDS) picture that advanced COVID-19 presents. 33 , 47 The deranged balance in the prothrombotic/antithrombotic properties of the endothelium can certainly contribute to thrombosis in situ in the pulmonary vasculature, as occurs in COVID-19. 48 Impaired gateway function of the endothelium for traversal of leucocytes into tissues clearly participates in pneumonitis.…”

Section: Cytokine Storm: a Perfect Storm In Covid-19mentioning

confidence: 99%

“…IL-1 not only induces leucocyte adhesion molecules but, by reducing VE-cadherin production, can contribute to impaired endothelial barrier function and thus capillary leak, a major issue that complicates COVID-19 pneumonitis. 47 Agents that inhibit the inflammasome–IL-1β–IL-6 pathway may thus comprise a more endothelial-directed approach to treatment of COVID-19. Some clinical trials that use such strategies have already yielded preliminary results; some, but not all, indicate signals of efficacy.…”

Section: Endothelial Functions As a Therapeutic Targetmentioning

confidence: 99%

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COVID-19 is, in the end, an endothelial disease

Libby

Lüscher

2020

European Heart Journal

783

805

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The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode. The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.

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Section: Cytokine Storm: a Perfect Storm In Covid-19mentioning

confidence: 99%

Section: Endothelial Functions As a Therapeutic Targetmentioning

confidence: 99%

COVID-19 is, in the end, an endothelial disease

Libby

Lüscher

2020

European Heart Journal

783

805

View full text Add to dashboard Cite

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“…The increased lipid peroxidation (LPO) in the sepsisassociated ALI has been observed (12). This increased LPO further activates CASP11, and thus, the GSDMD to cause the pyroptosis of AMs and infiltrated monocytes and macrophages in a phospholipase C gamma 1 (PLCG1)-dependent manner (234). Also, the inflammatory IL-1β reduces the cyclic adenosine monophosphate (cAMP) and transcription factor cAMP response element-binding (CREB) in lung endothelial cells (235).…”

Section: Alveolar Macrophages (Ams) and Sepsis-induced Ali//ardsmentioning

confidence: 99%

“…This increased LPO further activates CASP11, and thus, the GSDMD to cause the pyroptosis of AMs and infiltrated monocytes and macrophages in a phospholipase C gamma 1 (PLCG1)-dependent manner ( 234 ). Also, the inflammatory IL-1β reduces the cyclic adenosine monophosphate (cAMP) and transcription factor cAMP response element-binding (CREB) in lung endothelial cells ( 235 ). This CREB blockage inhibits the VE-cadherin transcription, which induces pulmonary vascular endothelial damage to aggravate pulmonary vascular leakage and sepsis-associated ALI.…”

Section: Pulmonary Innate Immune Response During Bacterial Sepsismentioning

confidence: 99%

“…This CREB blockage inhibits the VE-cadherin transcription, which induces pulmonary vascular endothelial damage to aggravate pulmonary vascular leakage and sepsis-associated ALI. Also, the treatment with rolipram (a drug inhibiting the type 4 cyclic nucleotide phosphodiesterase–mediated (PDE4-mediated) hydrolysis of cAMP) prevents sepsis-induced pulmonary vascular injury and thus the ALI via preserving the CREB-mediated VE-cadherin expression ( 235 ). Of note, the deficiency of neutrophils before sepsis also impairs the monocyte and macrophage infiltration in the lungs during both early and late stages and thus inflammatory process ( 236 ).…”

Section: Pulmonary Innate Immune Response During Bacterial Sepsismentioning

confidence: 99%

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Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury

2020

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The lung is a primary organ for gas exchange in mammals that represents the largest epithelial surface in direct contact with the external environment. It also serves as a crucial immune organ, which harbors both innate and adaptive immune cells to induce a potent immune response. Due to its direct contact with the outer environment, the lung serves as a primary target organ for many airborne pathogens, toxicants (aerosols), and allergens causing pneumonia, acute respiratory distress syndrome (ARDS), and acute lung injury or inflammation (ALI). The current review describes the immunological mechanisms responsible for bacterial pneumonia and sepsis-induced ALI. It highlights the immunological differences for the severity of bacterial sepsis-induced ALI as compared to the pneumonia-associated ALI. The immune-based differences between the Gram-positive and Gram-negative bacteria-induced pneumonia show different mechanisms to induce ALI. The role of pulmonary epithelial cells (PECs), alveolar macrophages (AMs), innate lymphoid cells (ILCs), and different pattern-recognition receptors (PRRs, including Toll-like receptors (TLRs) and inflammasome proteins) in neutrophil infiltration and ALI induction have been described during pneumonia and sepsis-induced ALI. Also, the resolution of inflammation is frequently observed during ALI associated with pneumonia, whereas sepsis-associated ALI lacks it. Hence, the review mainly describes the different immune mechanisms responsible for pneumonia and sepsis-induced ALI. The differences in immune response depending on the causal pathogen (Gram-positive or Gram-negative bacteria) associated pneumonia or sepsis-induced ALI should be taken in mind specific immune-based therapeutics.

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Surgical Treatment of Osteosarcoma Induced Distant Pre‐Metastatic Niche in Lung to Facilitate the Colonization of Circulating Tumor Cells

Tang,

Tie,

Lan

et al. 2023

Advanced Science

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Recently, the major challenge in treating osteosarcoma patients is the metastatic disease, most commonly in the lungs. However, the underlying mechanism of recurrence and metastasis of osteosarcoma after surgical resection of primary tumor remains unclear. This study aims to investigate whether the pulmonary metastases characteristic of osteosarcoma is associated with surgical treatment and whether surgery contributes to the formation of pre‐metastatic niche in the distant lung tissue. In the current study, the authors observe the presence of circulating tumor cells in patients undergoing surgical resection of osteosarcoma which is correlated to tumor recurrence. The pulmonary infiltrations of neutrophils and Gr‐1+ myeloid cells are characterized to form a pre‐metastatic niche upon the exposure of circulating tumor cells after surgical resection. It is found that mitochondrial damage‐associated molecular patterns released from surgical resection contribute to the formation of pre‐metastatic niche in lung through IL‐1β secretion. This study reveals that surgical management for osteosarcoma, irrespective of the primary tumor, might promote the formation of postoperative pre‐metastatic niche in lung which is with important implications for developing rational therapies during peri‐operative period.

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IL-1β suppression of VE-cadherin transcription underlies sepsis-induced inflammatory lung injury

Cited by 127 publications

References 55 publications

COVID-19 is, in the end, an endothelial disease

COVID-19 is, in the end, an endothelial disease

Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury

Surgical Treatment of Osteosarcoma Induced Distant Pre‐Metastatic Niche in Lung to Facilitate the Colonization of Circulating Tumor Cells

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