Combined CXCR1/CXCR2 Antagonism Decreases Radiation-Induced Alveolitis in the Mouse

Fox, Jessica K.; Gordon, John; Haston, Christina K.

doi:10.1667/rr2449.1

Cited by 16 publications

(14 citation statements)

References 33 publications

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“…Human umbilical vein ECs (HUVECs) irradiated in vitro secrete IL-8/CXCL8 [77]. As expected, antagonizing MIP-2/CXCL2 cognate receptors CXCR1/CXCR2 improved survival in a mouse model of radiation-induced alveolitis [78]. …”

Section: Reviewmentioning

confidence: 90%

Endothelial perturbations and therapeutic strategies in normal tissue radiation damage

Korpela

Liu

2014

Radiat Oncol

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Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Radiotherapy side-effects diminish patients’ quality of life, yet effective biological interventions for normal tissue damage are lacking. Protecting microvascular endothelial cells from the effects of irradiation is emerging as a targeted damage-reduction strategy. We illustrate the concept of the microvasculature as a mediator of overall normal tissue radiation toxicity through cell death, vascular inflammation (hemodynamic and molecular changes) and a change in functional capacity. Endothelial cell targeted therapies that protect against such endothelial cell perturbations and the development of acute normal tissue damage are mostly under preclinical development. Since acute radiation toxicity is a common clinical problem in cutaneous, gastrointestinal and mucosal tissues, we also focus on damage in these tissues.

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Section: Reviewmentioning

confidence: 90%

Endothelial perturbations and therapeutic strategies in normal tissue radiation damage

Korpela

Liu

2014

Radiat Oncol

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“…Other groups have also demonstrated that decreased neutrophil [12, 44], chemokine [12, 58] and pro-inflammatory cytokine levels [12, 44, 45] are associated with less radiation-induced skin damage. Specifically, antagonizing or inhibiting the receptor of MIP-2/CXCL2 improved survival in a mouse model of radiation-induced alveolitis [59] and sepsis [60]. …”

Section: Discussionmentioning

confidence: 99%

Vasculotide, an Angiopoietin-1 mimetic, reduces acute skin ionizing radiation damage in a preclinical mouse model

et al. 2014

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BackgroundMost cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Acute skin damage from cancer radiotherapy diminishes patients’ quality of life, yet effective biological interventions for this damage are lacking. Protecting microvascular endothelial cells from irradiation-induced perturbations is emerging as a targeted damage-reduction strategy. Since Angiopoetin-1 signaling through the Tie2 receptor on endothelial cells opposes microvascular perturbations in other disease contexts, we used a preclinical Angiopoietin-1 mimic called Vasculotide to investigate its effect on skin radiation toxicity using a preclinical model.MethodsAthymic mice were treated intraperitoneally with saline or Vasculotide and their flank skin was irradiated with a single large dose of ionizing radiation. Acute cutaneous damage and wound healing were evaluated by clinical skin grading, histology and immunostaining. Diffuse reflectance optical spectroscopy, myeloperoxidase-dependent bioluminescence imaging of neutrophils and a serum cytokine array were used to assess inflammation. Microvascular endothelial cell response to radiation was tested with in vitro clonogenic and Matrigel tubule formation assays. Tumour xenograft growth delay experiments were also performed. Appreciable differences between treatment groups were assessed mainly using parametric and non-parametric statistical tests comparing areas under curves, followed by post-hoc comparisons.ResultsIn vivo, different schedules of Vasculotide treatment reduced the size of the irradiation-induced wound. Although skin damage scores remained similar on individual days, Vasculotide administered post irradiation resulted in less skin damage overall. Vasculotide alleviated irradiation-induced inflammation in the form of reduced levels of oxygenated hemoglobin, myeloperoxidase bioluminescence and chemokine MIP-2. Surprisingly, Vasculotide-treated animals also had higher microvascular endothelial cell density in wound granulation tissue. In vitro, Vasculotide enhanced the survival and function of irradiated endothelial cells.ConclusionsVasculotide administration reduces acute skin radiation damage in mice, and may do so by affecting several biological processes. This radiation protection approach may have clinical impact for cancer radiotherapy patients by reducing the severity of their acute skin radiation damage.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-614) contains supplementary material, which is available to authorized users.

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“…CXCL8(3–74)K11R/G31P was also tested in a pig model of pulmonary aspiration and led to reduced pulmonary neutrophil response with significantly reduced pathology but still efficient pulmonary bacterial clearance [41]. Additionally, this specific antagonist reduced radiation-induced alveolitis, but not fibrosis [28]. …”

Section: Pharmacological Cxcr2 Blocking Strategiesmentioning

confidence: 99%

“…In CXCR2−/− mice, neutrophil migration to sites of inflammation is severely disturbed [27]. In experimental approaches, CXCR2 antagonism is able to attenuate tissue damage and disease progress; for example in radiation-induced alveolitis, sepsis, peritonitis and arthritis [28–31]. Modulation of the function of CXCR2 is therefore considered as a possible therapeutic strategy in the treatment of inflammatory conditions in humans [32].…”

Section: Introductionmentioning

confidence: 99%

CXCR2 in Acute Lung Injury

Konrad

Reutershan

2012

Mediators of Inflammation

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In pulmonary inflammation, recruitment of circulating polymorphonuclear leukocytes is essential for host defense and initiates the following specific immune response. One pathological hallmark of acute lung injury and acute respiratory distress syndrome is the uncontrolled transmigration of neutrophils into the lung interstitium and alveolar space. Thereby, the extravasation of leukocytes from the vascular system into the tissue is induced by chemokines that are released from the site of inflammation. The most relevant chemokine receptors of neutrophils are CXC chemokine receptor (CXCR) 1 and CXCR2. CXCR2 is of particular interest since several studies implicate a pivotal role of this receptor in development and promotion of numerous inflammatory disorders. CXCR2 gets activated by ELR+ chemokines, including MIP-2, KC (rodents) and IL-8 (human). Since multiple ELR+ CXC chemokines act on both receptors—CXCR1 and CXCR2—a pharmacologic agent blocking both receptors seems to be advantageous. So far, several CXCR1/2 antagonists have been developed and have been tested successfully in experimental studies. A newly designed CXCR1 and CXCR2 antagonist can be orally administered and was for the first time found efficient in humans. This review highlights the role of CXCR2 in acute lung injury and discusses its potential as a therapeutic target.

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Combined CXCR1/CXCR2 Antagonism Decreases Radiation-Induced Alveolitis in the Mouse

Cited by 16 publications

References 33 publications

Endothelial perturbations and therapeutic strategies in normal tissue radiation damage

Endothelial perturbations and therapeutic strategies in normal tissue radiation damage

Vasculotide, an Angiopoietin-1 mimetic, reduces acute skin ionizing radiation damage in a preclinical mouse model

CXCR2 in Acute Lung Injury

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