High concentrations of α-defensins in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome

Ashitani, Jun‐ichi; Mukae, Hiroshi; Arimura, Yasuji; Sano, Arisa; Tokojima, Masatoshi; Nakazato, Masamitsu

doi:10.1016/j.lfs.2004.01.028

Cited by 46 publications

(42 citation statements)

References 27 publications

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“…High concentrations of HNP associated with increased levels of IL-8 have been reported in the lung lavage fluid, sputum, and plasma of patients with a variety of inflammatory lung diseases. 6,7,41 We have demonstrated that HNPs at clinically relevant concentrations seen in the lung diseases can initiate inflammation by producing IL-8 and neutrophil migration, resulting in acute lung injury in vivo in mice. 33 Because HNPs are not direct chemoattractants for neutrophils, neutrophil infiltration is largely dependent on the release of IL-8 by lung epithelial cells in response to HNP stimulation.…”

Section: Discussionmentioning

confidence: 99%

“…30,31,45 Through the use of specific inhibitors, our results indicated that neither the P2X receptor nor the adenosine A 2b receptor played a significant role in mediating IL-8 production in response to HNP stimulation. Interestingly, a recent study demonstrated that the human cathelicidin-derived cationic peptide LL37, found in neutrophils, in bone marrow-derived cells, and in epithelial cells may promote IL-1␤ production in LPS-primed monocytes through the activation of P2X 7 receptors. 46 We demonstrate that the mRNAs of P2Y receptors P2Y 4 and P2Y 6 , but not P2Y 2 , express in lung epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…6 In patients with sepsis, HNP levels might be elevated to concentrations measured in milligrams per milliliter. 3 In lung lavage fluid, HNP concentrations were 50-fold higher in patients with ARDS than in healthy controls, 7 5 orders of magnitude greater in patients with bacterial pneumonia than in healthy volunteers, 6 and 31-fold higher in patients with diffuse panbronchiolitis than in controls. 8 In sputum, we have shown an HNP concentration of 240 Ϯ 40 g/mL in patients with cystic fibrosis compared with undetectable levels in healthy controls.…”

Section: Introductionmentioning

confidence: 97%

“…9 These and other studies showing increased levels of HNP in the circulation and in the airways of patients with inflammatory lung diseases suggest that HNPs may contribute to the pathogenesis of inflammatory lung disorders. [6][7][8][9][10][11][12] Indeed, in addition to their microbicidal role, extracellular HNPs can modulate immunologic responses. For example, HNPs are chemotactic to human CD4 ϩ /CD45RA ϩ naive T cells, CD8 ϩ T cells, immature human dendritic cells, 13 and monocytes.…”

Section: Introductionmentioning

confidence: 99%

“…P2X receptors are a family of adenosine triphosphate (ATP)-activated cation channels (P2X 1 to P2X 7 ) that open in response to ATP binding. 21 The P2Y family members are pertussis toxin-sensitive, G i -protein-coupled receptors.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway

Khine

Sorbo

Vaschetto

et al. 2006

Blood

106

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway

Khine

Sorbo

Vaschetto

et al. 2006

Blood

106

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Differential signaling mechanisms of HNP‐induced IL‐8 production in human lung epithelial cells and monocytes

Syeda

Liu

Tullis

et al. 2007

Journal Cellular Physiology

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Human neutrophil peptides (HNP) kill microorganisms but also modulate immune responses through upregulation of the chemokine IL-8 by activation of the nucleotide P2Y 6 receptor. However, the intracellular signaling mechanisms remain yet to be determined. Human lung epithelial cells (A549) and monocytes (U937) were stimulated with HNP in the absence and presence of the specific kinase inhibitors for Src, ERK1/2, p38 MAPK, JNK and Akt. HNP induced a rapid phosphorylation of the kinases in both cell types associated with a dosedependent, selective production of IL-8 among ten cytokines assayed. The HNP-induced IL-8 production was blocked by the Src tyrosine kinase inhibitor PP2, MEK1/2 inhibitor U0126 and the PI3K inhibitor LY294002, but not by the JNK inhibitor SP600125 in both cell types. Treatment with the p38 inhibitor SB203580 attenuated the HNP-induced IL-8 production only in monocytes. Blockade of Src kinase blunted HNP-induced phosphorylation of the ERK1/2 and Akt but not p38 in monocytes. In contrast, Src inhibition had no effect on phosphorylation of the other kinases in the lung epithelial cells. We conclude that the activation of ERK1/2 and PI3K/Akt pathways is required for HNP-induced IL-8 release which occurs in a Src-independent manner in lung epithelial cells, while is Src-dependent in monocytes.

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Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential

Potey

Rossi

Lucas

et al. 2019

The Journal of Pathology

198

154

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Acute respiratory distress syndrome (ARDS) is the often fatal sequelae of a broad range of precipitating conditions. Despite decades of intensive research and clinical trials there remain no therapies in routine clinical practice that target the dysregulated and overwhelming inflammatory response that characterises ARDS. Neutrophils play a central role in the initiation, propagation and resolution of this complex inflammatory environment by migrating into the lung and executing a variety of pro‐inflammatory functions. These include degranulation with liberation of bactericidal proteins, release of cytokines and reactive oxygen species as well as production of neutrophil extracellular traps. Although these functions are advantageous in clearing bacterial infection, the consequence of associated tissue damage, the contribution to worsening acute inflammation and prolonged neutrophil lifespan at sites of inflammation are deleterious. In this review, the importance of the neutrophil will be considered, together with discussion of recent advances in understanding neutrophil function and the factors that influence them throughout the phases of inflammation in ARDS. From a better understanding of neutrophils in this context, potential therapeutic targets are identified and discussed. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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High concentrations of α-defensins in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome

Cited by 46 publications

References 27 publications

Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway

Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway

Differential signaling mechanisms of HNP‐induced IL‐8 production in human lung epithelial cells and monocytes

Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential

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