Corrigendum: Environmental pressures, tumor characteristics, and death rate in a female breast cancer cohort: a seven-years Bayesian survival analysis using cancer registry data from a contaminated area in Italy.

[This corrects the article DOI: 10.3389/fpubh.2023.1310823.].

No Excess of Mortality from Lung Cancer during the COVID-19 Pandemic in an Area at Environmental Risk: Results of an Explorative Analysis.

BACKGROUND: The COVID-19 pandemic and the restrictive measures associated with it placed enormous pressure on health facilities and may have caused delays in the treatment of other diseases, leading to increases in mortality compared to the expected rates. Areas with high levels of air pollution already have a high risk of death from cancer, so we aimed to evaluate the possible indirect effects of the pandemic on mortality from lung cancer compared to the pre-pandemic period in the province of Taranto, a polluted site of national interest for environmental risk in the south of Italy. METHODS: We carried out a retrospective observational study on lung cancer data (ICD-10: C34) from the Registry of Mortality (ReMo) for municipalities in Taranto Province over the period of 1 January 2011 to 31 December 2021. Seasonal exponential smoothing, Holt-Winters additive, Holt-Winters multiplicative, and auto-regressive integrated moving average (ARIMA) models were used to forecast the number of deaths during the pandemic period. Data were standardized by sex and age via an indirect method and shown as monthly mortality rates (MRs), standardized mortality ratios (SMRs), and adjusted mortality rates (AMRs). RESULTS: In Taranto Province, 3108 deaths from lung cancer were recorded between 2011 and 2021. In the province of Taranto, almost all of the adjusted monthly mortality rates during the pandemic were within the confidence interval of the predicted rates, with the exception of significant excesses in March (+1.82, 95% CI 0.11-3.08) and August 2020 (+2.09, 95% CI 0.20-3.44). In the municipality of Taranto, the only significant excess rate was in August 2020 (+3.51, 95% CI 0.33-6.69). However, in total, in 2020 and 2021, the excess deaths from lung cancer were not significant both for the province of Taranto (+30 (95% CI -77; +106) for 2020 and +28 (95% CI -130; +133) for 2021) and for the municipality of Taranto alone (+14 (95% CI -47; +74) for 2020 and -2 (95% CI -86; +76) for 2021). CONCLUSIONS: This study shows that there was no excess mortality from lung cancer as a result of the COVID-19 pandemic in the province of Taranto. The strategies applied by the local oncological services during the pandemic were probably effective in minimizing the possible interruption of cancer treatment. Strategies for accessing care in future health emergencies should take into account the results of continuous monitoring of disease trends.

Environmental pressures, tumor characteristics, and death rate in a female breast cancer cohort: a seven-years Bayesian survival analysis using cancer registry data from a contaminated area in Italy.

Introduction: In Taranto, Southern Italy, adverse impacts on the environment and human health due to industrial installations have been studied. In the literature, few associations have been reported between environmental factors and breast cancer mortality in women. The aim of this study was to investigate the relationships between residence in areas with high environmental pressures, female breast cancer characteristics, and death rate. Methods: Data from the Taranto Cancer Registry were used, including all women with invasive breast cancer diagnosed between 01 January 2015 and 31 December 2020 and with follow-up to 31 December 2021. Bayesian mixed effects logistic and Cox regression models were fitted with the approach of integrated nested Laplace approximation, adjusting for patients and disease characteristics. Results: A total of 10,445 person-years were observed. Variables associated with higher death rate were residence in the contaminated site of national interest (SIN) (HR 1.22, 95% CrI 1.01-1.48), pathological/clinical stage III (HR 2.77, 95% CrI 1.93-3.97) and IV (HR 17.05, 95% CrI 11.94-24.34), histological grade 3 (HR 2.50, 95% CrI 1.20-5.23), Ki-67 proliferation index of 21-50% (HR 1.42, 95% CrI 1.10-1.83) and > 50% (HR 1.81, 95% CrI 1.29-2.55), and bilateral localization (HR 1.65, 95% CrI 1.01-2.68). Variables associated with lower death rate were estrogen and/or progesterone receptor positivity (HR 0.61, 95% CrI 0.45-0.81) and HER2/neu oncogene positivity (HR 0.59, 95% CrI 0.44-0.79). Discussion: The findings confirmed the independent prognostic values of different female breast cancer characteristics. Even after adjusting for patients and disease characteristics, residence in the SIN of Taranto appeared to be associated with an increased death rate.

Gender differences, environmental pressures, tumor characteristics, and death rate in a lung cancer cohort: a seven-years Bayesian survival analysis using cancer registry data from a contaminated area in Italy.

Introduction: In Taranto, Southern Italy, adverse impacts on the environment and human health due to industrial installations have been studied. In the literature, associations have been reported between gender, environmental factors, and lung cancer mortality in women and men. The aim of this study was to investigate the relationships between gender, residence in areas with high environmental pressures, bronchus/lung cancer characteristics, and death rate. Methods: Data from the Taranto Cancer Registry were used, including all women and men with invasive bronchus/lung cancer diagnosed between 1 January 2016 and 31 December 2020 and with follow-up to 31 December 2022. Bayesian mixed effects logistic and Cox regression models were fitted with the approach of integrated nested Laplace approximation, adjusting for patients and disease characteristics. Results: A total of 2,535 person-years were observed. Male gender was associated with a higher prevalence of histological grade 3 (OR 2.45, 95% CrI 1.35-4.43) and lung squamous-cell carcinoma (OR 3.04, 95% CrI 1.97-4.69). Variables associated with higher death rate were male gender (HR 1.24, 95% CrI 1.07-1.43), pathological/clinical stage II (HR 2.49, 95% CrI 1.63-3.79), III (HR 3.40, 95% CrI 2.33-4.97), and IV (HR 8.21, 95% CrI 5.95-11.34), histological grade 3 (HR 1.80, 95% CrI 1.25-2.59), lung squamous-cell carcinoma (HR 1.18, 95% CrI 1.00-1.39), and small-cell lung cancer (HR 1.62, 95% CrI 1.31-1.99). Variables associated with lower death rate were other-type lung cancer (HR 0.65, 95% CrI 0.44-0.95), high immune checkpoint ligand expression (HR 0.75, 95% CrI 0.59-0.95), lung localization (HR 0.73, 95% CrI 0.62-0.86), and left localization (HR 0.85, 95% CrI 0.75-0.95). Discussion: The results among patients with lung cancer did not show an association between residence in the contaminated site of national interest (SIN) and the prevalence of the above mentioned prognostic factors, nor between residence in SIN and death rate. The findings confirmed the independent prognostic values of different lung cancer characteristics. Even after adjusting for patients and disease characteristics, male gender appeared to be associated with a higher prevalence of poorly differentiated cancer and squamous-cell carcinoma, and with an increased death rate.

Time-dependent benefits of pre-treatment with new oral P2Y12 -inhibitors in patients addressed to primary PCI for acute ST-elevation myocardial infarction.

OBJECTIVES: The aim of this observational study was to determine the benefits of the novel, orally delivered P2Y12 -inhibitors (Is) in terms of angiographic endpoints and in relation to the time of the loading dose (LD) administration. BACKGROUND: The goal of ST-elevation myocardial infarction (STEMI) treatment is timely reperfusion. The P2Y12 -Is prasugrel and ticagrelor have improved the angiographic outcome of primary percutaneous coronary intervention (pPCI) and patients' prognosis. However, their onset of action is impaired in STEMI and delayed by their oral administration. METHODS: The 328 eligible patients with STEMI consecutively referred for pPCI were divided into three groups depending on the interval of "P2Y12 -I LD administration-to-balloon time": Group 2 included patients that received P2Y12 -I LD at least 60 min prior to pPCI, Group 1 within 60 min prior to pPCI, and Group 0 at the moment of pPCI. Angiographic, clinical, and biochemical parameters were evaluated. Pre- and post-pPCI TIMI flow grade (TFG) and ST resolution (STR) were used as outcome measures to determine efficacy and optimal timing of pretreatment. RESULTS: Pre-pPCI TFG improved with increasing P2Y12 -I LD administration-to-balloon time; pre-PCI TFG 0/1 was 74.5% in Group 0, 65.5% in Group 1 and 54.9% in Group 2 (P < 0.002). Post-pPCI TFG 3 results also differed significantly between the three groups: 85.2% in Group 0, 88.1% in Group 1, 97.6% in Group 2 (P < 0.013). ST resolution rates were also positively associated with longer pretreatment intervals. CONCLUSIONS: This observational study suggests that the angiographic benefit of P2Y12 -I administration is time-dependent: longer pretreatment improves coronary reperfusion in terms of pre- and post-pPCI TFG and STR.

Primary polymorphous hemangioendothelioma of the maxillary soft tissue: clinical and immunopathological aspects of a rare vascular neoplasm.

Polymorphous hemangioendothelioma (PH) is an uncommon vascular neoplasm of borderline malignant potential characterized by a considerable variability in patterns of cellular growth. Morphologically, PH may be confused with other lesions, from benign vasoformative neoplasms and reactive inflammatory conditions to malignancies such as angiosarcoma or squamous cell carcinoma. Most occur in the lymph nodes, and to the best of our knowledge, lesions involving the maxillary soft tissue have not been described in the literature to date. A potential for local recurrence, as well as the ability to metastasize, has been for this type of neoplasm. Here we reported on a rare case of polymorphous hemangioendothelioma which presented as an asymptomatic subcutaneous mass in the right zygomatic region of a 22-year-old white female. We discuss the histopathological aspects of this tumor, with emphasis on the role of immunohistochemical analysis in differential diagnosis.

Administration of reconstituted polyphenol oil bodies efficiently suppresses dendritic cell inflammatory pathways and acute intestinal inflammation.

Polyphenols are natural compounds capable of interfering with the inflammatory pathways of several in vitro model systems. In this study, we developed a stable and effective strategy to administer polyphenols to treat in vivo models of acute intestinal inflammation. The in vitro suppressive properties of several polyphenols were first tested and compared for dendritic cells (DCs) production of inflammatory cytokines. A combination of the polyphenols, quercetin and piperine, were then encapsulated into reconstituted oil bodies (OBs) in order to increase their stability. Our results showed that administration of low dose reconstituted polyphenol OBs inhibited LPS-mediated inflammatory cytokine secretion, including IL-6, IL-23, and IL-12, while increasing IL-10 and IL-1Rα production. Mice treated with the polyphenol-containing reconstituted OBs (ROBs) were partially protected from dextran sodium sulfate (DSS)-induced colitis and associated weight loss, while mortality and inflammatory scores revealed an overall anti-inflammatory effect that was likely mediated by impaired DC immune responses. Our study indicates that the administration of reconstituted quercetin and piperine-containing OBs may represent an effective and potent anti-inflammatory strategy to treat acute intestinal inflammation.

Augmented corticotomy combined with accelerated orthodontic forces in class III orthognathic patients: morphologic aspects of the mandibular anterior ridge with cone-beam computed tomography.

PURPOSE: This study used cone-beam computed tomography to evaluate morphologic changes of the mandibular anterior ridge after using augmented corticotomy plus accelerated orthodontia to decompensate mandibular incisors in patients with surgical skeletal Class III. MATERIALS AND METHODS: Fourteen patients (8 men, 6 women; mean age, 26.14 yr) with skeletal Class III were treated before orthognathic surgery with a technique that combined corticotomy, bone grafting, and accelerated orthodontic forces to decompensate the lower incisors. Three-dimensional cone-beam computed tomograms were taken before treatment (T0) and at the completion of presurgical orthodontic treatment (T1). Measurements of the amount of vertical alveolar bone changes and horizontal bone thickness at the midroot and root apex levels of the mandibular incisors were evaluated. RESULTS: All patients showed significant proclination of the mandibular incisors at T1. The mean alveolar bone thickness from T0 to T1 increased buccally at the midroot and apex levels, showing statistically significant horizontal bone augmentation at the labial side of the lower anterior mandibular teeth (P < .05). The mean amount of vertical bone change did not show any significant vertical loss of alveolar bone. CONCLUSION: This new combined technique provided adequate decompensation of the mandibular incisors by increasing horizontal bone thickness in the labial aspect of the mandibular anterior area, without any vertical bone loss. This approach decreases the risk of the typical periodontal complications associated with traditional orthodontics, such as marginal bone loss and gingival recession.

Piezoelectric device vs. conventional rotative instruments in impacted third molar surgery: relationships between surgical difficulty and postoperative pain with histological evaluations.

PURPOSE: To investigate and compare the influence of surgical difficulty on postoperative pain after treatment of impacted mandibular third molars by rotatory osteotomy or Piezoelectric surgery. MATERIALS AND METHODS: A prospective, randomized, split-mouth study was performed of 52 patients with bilateral and symmetrically oriented impacted mandibular third molars, who were surgically treated using a burr (Group A) on one random side of the lower jaw and a Piezoelectric device (Group B) on the contralateral side. Surgical difficulty was evaluated using a modified version of the Parant scale to categorize "simple extractions" and "complex extractions". Primary outcome parameters were the comparison of the postoperative pain evaluation rated on the Visual Analogue Scale from day 0 to day 6 postsurgery, and the assessment of differences in surgery time between the groups. Bone biopsies were taken during surgery to assess differences in bone tissue damage levels between the two different techniques. RESULTS: In "complex extractions" lower pain evaluation and significantly shorter surgery times were recorded when rotatory instruments were used. In "simple extractions", similar surgery times were observed for both techniques, but pain was greatest on the day of surgery when the burr was used. Bone heat osteonecrosis was observed only in the rotatory group and a high level of alkaline phosphatase was noted only in the Piezoelectric group. CONCLUSION: Pain after extraction of a mandibular third molar increases with increased surgical difficulty and especially in longer interventions. The integrity of the bony structure observed after the ultrasonic technique may favour the bone healing process.

Use of intermaxillary forces in early treatment of maxillary deficient class III patients: results of a case series.

INTRODUCTION: The early treatment of Class III malocclusion with a protraction facemask can produce forward movement of the maxilla but is generally associated with posterior rotation of the mandible and dentoalveolar compensations. This article shows the dental and skeletal effects of intermaxillary elastics applied to temporary anchorage devices in the treatment of maxillary deficient Class III patients. MATERIALS AND METHODS: A total of 6 patients with skeletal Class III malocclusion were treated with intermaxillary elastics only. This traction was applied between modified miniplates placed in the maxilla and a modified lower acrylic resin plate bonded on mandibular tooth surfaces. To evaluate the orthodontic changes, lateral cephalograms were taken at the start of the treatment (T1), at the end of the orthopaedic treatment (T2) and at the follow-up (T3). RESULTS: All patients showed orthopaedic correction of the skeletal Class III relationship with reduction of facial concavity. No dentoalveolar compensations or changes in mandibular position were observed. CONCLUSION: The treatment of maxillary deficiency with orthopaedic forces from skeletal anchorage directed to the hooks of a modified lower acrylic resin plate bonded on the mandibular tooth surfaces, seems to be a promising technique.

Oral fibrous histiocytoma and its angiomatoid variant.

Fibrous histiocytomas are uncommon mesenchymal tumours of the soft tissue in the head and neck region. We report two cases that occurred in the oral cavity, one of a benign fibrous histiocytoma (BFH) and another of an angiomatoid variant of fibrous histiocytoma (AFH). BFH is a benign neoplasm composed of cells with fibroblastic and histiocytic characteristics, while AFH is considered as a distinct type of fibrous histiocytoma with an intermediate malignancy grade that combines features of both fibrohistiocytic and vascular neoplasm. We describe the clinicopathological and histological characteristics of these lesions to clarify and facilitate their diagnosis. In the BFH case, the surgical specimen had many histiocytes positive for lysozime, whereas the AFH cells showed positivity for endothelial cell marker (anti-CD34 antibody). In both cases the tumours were positive for fibronectin and negative for S100 and SMA. Ki-67. Immunohistochemistry was performed in all cases to reveal the different mitotic activity between AFH and BFH tumour cells. Finally, differential diagnoses and therapeutic treatments are discussed.

Whole blood transcriptomics in cardiac surgery identifies a gene regulatory network connecting ischemia reperfusion with systemic inflammation.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CS/CPB) is associated with increased risk for postoperative complications causing substantial morbidity and mortality. To identify the molecular mechanisms underlying CS/CPB-induced pathophysiology we employed an integrative systems biology approach using the whole blood transcriptome as the sentinel organ. METHODOLOGY/PRINCIPAL FINDINGS: Total RNA was isolated and globin mRNA depleted from whole blood samples prospectively collected from 10 patients at time points prior (0), 2 and 24 hours following CS/CPB. Genome-wide transcriptional analysis revealed differential expression of 610 genes after CS/CPB (p<0.01). Among the 375 CS/CPB-upregulated genes, we found a gene-regulatory network consisting of 50 genes, reminiscent of activation of a coordinated genetic program triggered by CS/CPB. Intriguingly, the highly connected hub nodes of the identified network included key sensors of ischemia-reperfusion (HIF-1alpha and C/EBPbeta). Activation of this network initiated a concerted inflammatory response via upregulation of TLR-4/5, IL1R2/IL1RAP, IL6, IL18/IL18R1/IL18RAP, MMP9, HGF/HGFR, CalgranulinA/B, and coagulation factors F5/F12 among others. Differential regulation of 13 candidate genes including novel, not hitherto CS/CBP-associated genes, such as PTX3, PGK1 and Resistin, was confirmed using real-time quantitative RT-PCR. In support of the mRNA data, differential expression of MMP9, MIP1alpha and MIP1beta plasma proteins was further confirmed in 34 additional patients. CONCLUSIONS: Analysis of blood transcriptome uncovered critical signaling pathways governing the CS/CPB-induced pathophysiology. The molecular signaling underlying ischemia reperfusion and inflammatory response is highly intertwined and includes pro-inflammatory as well as cardioprotective elements. The herein identified candidate genes and pathways may provide promising prognostic biomarker and therapeutic targets.

Mesenchymal stem cells, used as bait, disclose tissue binding sites: a tool in the search for the niche?

We developed an ex vivo approach characterizing renal mesenchymal stem cell (MSC) adhesion to kidney sections. Specificity of MSC adhesion was confirmed by demonstrating a) 3T3 cells displayed 10-fold lower adhesion, and b) MSC adhesion was CXCR4/stromal-derived factor-1 (SDF-1)-dependent. MSC adhesion was asymmetrical, with postischemic sections exhibiting more than twofold higher adhesion than controls, and showed preference to perivascular areas. Pretreating kidney sections with cyclic arginine-glycine-aspartic acid peptide resulted in increased MSC adhesion (by displacing resident cells), whereas blockade of CXCR4 with AMD3100 and inhibition of alpha4beta1(VLA4) integrin or vascular cellular adhesion molecule-1, reduced adhesion. The difference between adhered cells under cyclic arginine-glycine-aspartic acid peptide-treated and control conditions reflected prior occupancy of binding sites with endogenous cells. The AMD3100-inhibitable fraction of adhesion reflected CXCR4-dependent adhesion, whereas maximal adhesion was interpreted as kidney MSC-lodging capacity. MSC obtained from mice overexpressing caveolin-1 exhibited more robust adhesion than those obtained from knockout animals, consistent with CXCR4 dimerization in caveolae. These data demonstrate a) CXCR4/SDF-1-dependent adhesion increases in ischemia; b) CXCR4/SDF-1 activation is dependent on MSC surface caveolin-1; and c) occupancy of MSC binding sites is decreased, while d) capacity of MSC binding sites is expanded in postischemic kidneys. In conclusion, we developed a cell-bait strategy to unmask renal stem cell binding sites, which may potentially shed light on the MSC niche(s) and its characteristics.

Exploration of disease mechanism in acute kidney injury using a multiplex bead array assay: a nested case-control pilot study.

BACKGROUND: Acute kidney injury (AKI) following cardiac surgery with cardiopulmonary bypass (CPB) causes increased morbidity and mortality. OBJECTIVE: To evaluate the plasma profile of biomarkers potentially involved in AKI development following CPB. METHODS: In a nested case-control study, plasma levels of 27 biomarkers in 11 AKI cases were compared with 25 controls. RESULTS: Pre-CPB, plasma levels of epidermal growth factor and macrophage inflammatory protein-1beta, 2 h following CPB, soluble vascular cell adhesion molecule-1 (sVCAM-1), fractalkine and macrophage inflammatory protein-1alpha, and at later time points, sVCAM-1 and interleukin-6 were associated with AKI. CONCLUSION: Biomarkers associated with AKI following CPB may merit further study.

Enhanced progenitor cell recruitment and endothelial repair after selective endothelial injury of the mouse kidney.

Primary and/or secondary injury of the renal microvascular endothelium is a common finding in various renal diseases. Besides well-known endothelial repair mechanisms, including endothelial cell (EC) proliferation and migration, homing of extrinsic cells such as endothelial progenitor cells (EPC) and hematopoietic stem cells (HSC) has been shown in various organs and may contribute to microvascular repair. However, these mechanisms have so far not been studied after selective microvascular injury in the kidney. The present study investigated the time course of EPC and HSC stimulation and homing following induction of selective EC injury in the mouse kidney along with various angiogenic factors potentially involved in EC repair and progenitor cell stimulation. Erythropoietin was used to stimulate progenitor cells in a therapeutic approach. We found that selective EC injury leads to a marked stimulation of EPCs, HSCs, and various angiogenic factors to orchestrate microvascular repair. Angiogenic factors started to increase as early as 30 min after disease induction. Progenitor cells could be first detected in the circulation and the spleen before they selectively homed to the diseased kidney. Injection of a high dose of erythropoietin 2 h after disease induction markedly attenuated vascular injury through nonhemodynamic mechanisms, possibly involving vascular endothelial growth factor release.

Adriamycin nephropathy: a failure of endothelial progenitor cell-induced repair.

Adriamycin-associated nephropathy (AAN) remains poorly understood. We hypothesized that adriamycin affects endothelial progenitor cells (EPCs), leading to impaired regeneration. We analyzed renal hematopoietic stem cells (HSCs) and EPCs in mice with AAN and examined the potential contribution of adoptive transfer of intact EPCs to the repair processes. FACS analyses revealed that populations of HSCs and EPCs were scarcely represented in control kidneys and did not change numerically in kidneys obtained from mice with AAN. The observed defect in engraftment was attributable to the decreased viability and increased senescence of EPCs. Adoptive transfer of intact EPCs improved proteinuria and renal function, with a threefold decrease in mortality. Infusion of EPCs to adriamycin-treated mice reduced plasma levels of interleukin-1alpha and -beta and granulocyte-colony stimulating factor as well as increased the level of vascular endothelial growth factor with concomitant improvement of vascular density and reduction of apoptosis. An additional mechanism of tissue repair is proposed based on tunneling nanotube formation between EPCs and endothelial cells exposed to adriamycin, leading to the multiple rounds of exchange between EPCs and mature cells. In conclusion, AAN is associated with development of EPC incompetence; adoptive transfer of intact EPCs blunts morphological and functional manifestations of AAN; and the proposed mechanisms of repair by EPCs include direct incorporation into blood vessels, paracrine signaling, and tunneling nanotube renewal of mitochondrial pool in endothelial cells.

Adoptive transfer of syngeneic bone marrow-derived cells in mice with obesity-induced diabetes: selenoorganic antioxidant ebselen restores stem cell competence.

There are conflicting data regarding the effects of transplantation of bone marrow-derived cells (BMDCs) on the severity of diabetes. We therefore inquired whether the competence of BMDCs is preserved on adoptive transfer into diabetic (db/db) mice and how the adoptive transfer of BMDCs affects vascular and metabolic abnormalities in these mice. Recipient db/db mice received infusions of BMDCs prepared from either db/db or non-diabetic heterozygout mice (db/m) mice and effects on endothelium-dependent relaxation, insulin sensitivity, and renal function were evaluated. Recipients of BMDCs from db/m, but not db/db donors showed better glucose control, exhibited striking improvement in endothelium-dependent relaxation in response to acetylcholine, and had partially restored renal function. Improved glucose control was due to enhanced insulin sensitivity, most likely secondary to improved vascular function. Enhanced apoptosis of endothelial progenitor cells under oxidative stress, as well as decreased endothelial progenitor cell numbers were responsible for the apparent functional incompetence of BMDCs from db/db donors. Treatment of db/db mice with Ebselen restored the resistance of both BMDCs and endothelial progenitor cells to oxidative stress, improved acetylcholine-induced vasorelaxation, and reduced proteinuria in db/db recipients of BMDC transplantation. In conclusion, infusion of BMDCs obtained from db/m donors to db/db recipient mice benefited macrovascular function, insulin sensitivity, and nephropathy. BMDCs obtained from db/db mice were functionally incompetent secondary to the increased proportion of apoptotic cells on oxidative stress challenge; their competence was restored by Ebselen therapy.

Ischemia-induced exocytosis of Weibel-Palade bodies mobilizes stem cells.

Recruitment of various stem and progenitor cells is crucial for the regeneration of an injured organ. Levels of uric acid, one of the prototypical "alarm signals," surge after ischemia-reperfusion injury. Exogenous uric acid rapidly mobilizes endothelial progenitor cells and hematopoietic stem cells and protects the kidney from ischemia. The relatively fast responses to uric acid suggest that preformed second messengers may be released from a storage pool. Here, it is reported that monosodium urate (MSU) results in exocytosis of Weibel-Palade bodies in vitro and in vivo, leading to the release of IL-8, von Willebrand factor, and angiopoietin 2 in the culture medium or circulation. Confocal and immunoelectron microscopy confirmed depletion of von Willebrand factor in MSU-treated aortic endothelial cells. Angiopoietin 2 alone induced exocytosis of Weibel-Palade bodies, mobilized hematopoietic stem cells and depleted splenic endothelial progenitor cells, partially reproducing the actions of MSU. In addition, pretreatment with angiopoietin 2 protected the kidneys from an ischemic insult, suggesting that the previously reported renoprotection conferred by MSU likely results from exocytosis of Weibel-Palade bodies. Furthermore, experiments with toll-like receptor 4 (TLR-4)-and TLR-2-deficient mice demonstrated that uric acid-induced exocytosis of Weibel-Palade bodies is mediated by TLR-4 and that uric acid-induced release of IL-8 requires both TLR-2 and TLR-4. In summary, these results suggest that exocytosis of Weibel-Palade bodies links postischemic repair with inflammation and mobilization of stem cells.