Editor’s Highlight: Role of Spleen-Derived Macrophages in Ozone-Induced Lung Inflammation and Injury

Francis, Mary; Sun, Richard; Cervelli, Jessica A.; Choi, Hyeon‐Son; Mandal, Mili; Abramova, Elena; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

doi:10.1093/toxsci/kfw192

Cited by 28 publications

(19 citation statements)

References 51 publications

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“…These results corroborate previous findings in a rat model of CPB [ 29 , 30 ]. Our findings did not show a significant increase in pulmonary macrophage infiltration, which is in concordance with previous work done by Francis et al [ 31 ] who found a significant increase in macrophage infiltration as late as 24–48 h after induction of lung injury. In future studies, longer follow up is planned to compare the macrophage activation to previous studies.…”

Section: Discussionsupporting

confidence: 94%

Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

et al. 2018

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Cardiopulmonary bypass (CPB) with moderate hypothermic cardiac arrest (MHCA) is essential for prolonged complex procedures in cardiac surgery and is associated with postoperative complications. Although cytokine release provoked through MHCA under CPB plays a pivotal role in postoperative organ damage, the pathomechanisms are unclear. Here, we investigated the cytokine release pattern and histological organ damage after MHCA using a recently described mouse CPB model. Eight BALB/c mice underwent 60 minutes of circulatory arrest under CPB, were successively rewarmed and reperfused. Blood cytokine concentrations and liver and kidney function parameters were measured and histological changes to these organs were compared to control animals. Our results showed a marked increase in proinflammatory cytokines and histological changes in the kidney, lung, and liver after CPB. Furthermore, clinical chemistry showed signs of hemolysis and acute kidney injury. These results suggest early onset of solid organ injury which correlates with increased leukocyte infiltration. A better understanding of the interplay between pro-inflammatory cytokine activation and solid organ injury in this model of CBP with MHCA will inform strategies to reduce organ damage during cardiac surgeries in the clinic.

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Section: Discussionsupporting

confidence: 94%

Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

et al. 2018

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“…The spleen is necessary for the recruitment of classical monocytes and neutrophil extravasation into the injured lung. Both bone marrow and spleen are sites where monocytes can be recruited from in models of lung inflammation (30). We first set out to analyze classical monocytes in different compartments following lung IRI.…”

Section: Resultsmentioning

confidence: 99%

Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1β

Hsiao

Fernández

Tanaka

et al. 2018

Journal of Clinical Investigation

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Ischemia-reperfusion injury, a form of sterile inflammation, is the leading risk factor for both short-term mortality following pulmonary transplantation and chronic lung allograft dysfunction. While it is well recognized that neutrophils are critical mediators of acute lung injury, processes that guide their entry into pulmonary tissue are not well understood. Here, we found that CCR2+ classical monocytes are necessary and sufficient for mediating extravasation of neutrophils into pulmonary tissue during ischemia-reperfusion injury following hilar clamping or lung transplantation. The classical monocytes were mobilized from the host spleen, and splenectomy attenuated the recruitment of classical monocytes as well as the entry of neutrophils into injured lung tissue, which was associated with improved graft function. Neutrophil extravasation was mediated by MyD88-dependent IL-1β production by graft-infiltrating classical monocytes, which downregulated the expression of the tight junction-associated protein ZO-2 in pulmonary vascular endothelial cells. Thus, we have uncovered a crucial role for classical monocytes, mobilized from the spleen, in mediating neutrophil extravasation, with potential implications for targeting of recipient classical monocytes to ameliorate pulmonary ischemia-reperfusion injury in the clinic.

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“…Both tissue compartments we analyzed are heterogeneous, which cannot be easily accounted for using bulk RNA-seq. Flow sorting or single-cell RNA-seq could be used to assign AM origin and phenotype, particularly after O3 exposure when inflammatory monocytes have been recruited from the periphery (FRANCIS et al 2017a;FRANCIS et al 2017b). Likewise, these approaches could be applied for the many cell types that comprise the airways and resident and/or recruited immune cell populations that are tightly associated with or interdigitated within the epithelium.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of the murine airway response to acute ozone exposure

Tovar

Smith

Thomas

et al. 2019

Preprint

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Exposure to ambient ozone (O3) pollution causes airway inflammation, epithelial injury, and decreased lung function. Long-term exposure is associated with increased mortality and exacerbations of respiratory conditions. While the adverse health effects of O3 exposure have been thoroughly described, less is known about the molecular processes that drive these outcomes. The aim of this study was to describe the cellular and molecular alterations observed in murine airways after exposure to either 1 or 2 ppm O3. After exposing adult, female C57BL/6J mice to filtered air, 1 or 2 ppm O3 for 3 hours, we assessed hallmark responses including airway inflammatory cell counts, epithelial permeability, cytokine secretion, and morphological alterations of the large airways. Further, we performed RNA-seq to profile gene expression in two critical tissues involved in O3 responses: conducting airways (CA) and airway macrophages (AM). We observed a concentration-dependent increase in airway inflammation and injury, and a large number of genes were differentially expressed in both target tissues at both concentrations of O3. Genes that were differentially expressed in CA were generally associated with barrier function, detoxification processes, and cellular proliferation. The differentially expressed genes in AM were associated with innate immune signaling, cytokine production, and extracellular matrix remodeling. Overall, our study has described transcriptional responses to acute O3 exposure, revealing both shared and unique gene expression patterns across multiple concentrations of O3 and in two important O3-responsive tissues. These profiles provide broad mechanistic insight into pulmonary O3 toxicity, and reveal a variety of targets for refined followup studies.

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Editor’s Highlight: Role of Spleen-Derived Macrophages in Ozone-Induced Lung Inflammation and Injury

Cited by 28 publications

References 51 publications

Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass

Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1β

Transcriptional profiling of the murine airway response to acute ozone exposure

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