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      FPR-1 is an important regulator of neutrophil recruitment and a tissue-specific driver of pulmonary fibrosis

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          Abstract

          Neutrophils are the most abundant inflammatory cells at the earliest stages of wound healing and play important roles in wound repair and fibrosis. Formyl peptide receptor 1 (FPR-1) is abundantly expressed on neutrophils and has been shown to regulate their function, yet the importance of FPR-1 in fibrosis remains ill defined. FPR-1–deficient ( fpr1 –/– ) mice were protected from bleomycin-induced pulmonary fibrosis but developed renal and hepatic fibrosis normally. Mechanistically, we observed a failure to effectively recruit neutrophils to the lungs of fpr1 –/– mice, whereas neutrophil recruitment was unaffected in the liver and kidney. Using an adoptive transfer model we demonstrated that the defect in neutrophil recruitment to the lung was intrinsic to the fpr1 –/– neutrophils, as C57BL/6 neutrophils were recruited normally to the damaged lung in fpr1 –/– mice. Finally, C57BL/6 mice in which neutrophils had been depleted were protected from pulmonary fibrosis. In conclusion, FPR-1 and FPR-1 ligands are required for effective neutrophil recruitment to the damaged lung. Failure to recruit neutrophils or depletion of neutrophils protects from pulmonary fibrosis.

          Abstract

          FPR-1 is the primary receptor driving neutrophil recruitment to the injured lung, and absence of FPR-1 or depletion of neutrophils protects from pulmonary fibrosis.

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          Most cited references40

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          Neutrophils and Wound Repair: Positive Actions and Negative Reactions.

          Neutrophils are one of the most abundant cells of the immune system and they are extremely active during the repair of cutaneous wounds. In general, the antimicrobial activity of neutrophils is effective and allows these cells to carry out their primary function of preventing wounds from becoming infected.
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            Animal models of fibrotic lung disease.

            Interstitial lung fibrosis can develop as a consequence of occupational or medical exposure, as a result of genetic defects, and after trauma or acute lung injury leading to fibroproliferative acute respiratory distress syndrome, or it can develop in an idiopathic manner. The pathogenesis of each form of lung fibrosis remains poorly understood. They each result in a progressive loss of lung function with increasing dyspnea, and most forms ultimately result in mortality. To better understand the pathogenesis of lung fibrotic disorders, multiple animal models have been developed. This review summarizes the common and emerging models of lung fibrosis to highlight their usefulness in understanding the cell-cell and soluble mediator interactions that drive fibrotic responses. Recent advances have allowed for the development of models to study targeted injuries of Type II alveolar epithelial cells, fibroblastic autonomous effects, and targeted genetic defects. Repetitive dosing in some models has more closely mimicked the pathology of human fibrotic lung disease. We also have a much better understanding of the fact that the aged lung has increased susceptibility to fibrosis. Each of the models reviewed in this report offers a powerful tool for studying some aspect of fibrotic lung disease.
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              Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.

              We have demonstrated that caspase-1-deficient (caspase-1(-/-)) mice are functionally and histologically protected against cisplatin-induced acute renal failure (ARF). Caspase-1 exerts proinflammatory effects via the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil recruitment. We sought to determine the role of the cytokines IL-1beta, IL-18, and IL-6 and neutrophil recruitment in cisplatin-induced ARF. We first examined IL-1beta; renal IL-1beta increased nearly 2-fold in cisplatin-induced ARF and was reduced in the caspase-1(-/-) mice. However, inhibition with IL-1 receptor antagonist (IL-1Ra) did not attenuate cisplatin-induced ARF. Renal IL-18 increased 2.5-fold; however, methods to inhibit IL-18 using IL-18 antiserum and transgenic mice that overproduce IL-18-binding protein (a natural inhibitor of IL-18) did not protect. Renal IL-6 increased 3-fold; however, IL-6-deficient (IL-6(-/-)) mice still developed cisplatin-induced ARF. We next examined neutrophils; blood neutrophils increased dramatically after cisplatin injection; however, prevention of peripheral neutrophilia and renal neutrophil infiltration with the neutrophil-depleting antibody RB6-8C5 did not protect against cisplatin-induced ARF. In summary, our data demonstrated that cisplatin-induced ARF is associated with increases in the cytokines IL-1beta, IL-18, and IL-6 and neutrophil infiltration in the kidney. However, inhibition of IL-1beta, IL-18, and IL-6 or neutrophil infiltration in the kidney is not sufficient to prevent cisplatin-induced ARF.
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                Author and article information

                Contributors
                Journal
                JCI Insight
                JCI Insight
                JCI Insight
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                27 February 2020
                27 February 2020
                27 February 2020
                : 5
                : 4
                : e125937
                Affiliations
                [1 ]Newcastle Fibrosis Research Group and
                [2 ]Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
                [3 ]Interstitial Lung Disease Clinic, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
                [4 ]Firestone Institute for Respiratory Health, Saint Joseph’s Healthcare and Department of Pathology and Molecular Medicine, McMaster University Hamilton, Hamilton, Ontario, Canada.
                [5 ]MedImmune Ltd., Cambridge, United Kingdom.
                [6 ]Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, United Kingdom.
                Author notes
                Address correspondence to: Lee Borthwick, Newcastle Fibrosis Research Group, Biosciences Institute, 4th Floor, William Leech Building, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom. Phone: 0191.208.3112; Email: lee.borthwick@ 123456ncl.ac.uk .

                Authorship note: JL and BJMM contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-6443-2396
                http://orcid.org/0000-0002-7510-6737
                http://orcid.org/0000-0003-4879-966X
                http://orcid.org/0000-0001-8692-1836
                http://orcid.org/0000-0003-4822-7223
                Article
                125937
                10.1172/jci.insight.125937
                7101152
                32102985
                0c231105-aa90-46e8-95d0-f75001bb7760
                © 2020 Leslie et al.

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 November 2018
                : 15 January 2020
                Funding
                Funded by: Medical Research Council (MRC)
                Award ID: MR/R023026/1
                Funded by: Cancer Research UK (CRUK)
                Award ID: C18342/A23390
                Funded by: Wellcome Trust
                Award ID: 204787/Z/16/Z
                Funded by: MedImmune Ltd
                Award ID: n/a
                Categories
                Research Article

                cell biology,immunology,fibrosis,neutrophils
                cell biology, immunology, fibrosis, neutrophils

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