{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:19:08Z","timestamp":1789676348821,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases (NIAID)","award":["5R03AI135346-02"],"award-info":[{"award-number":["5R03AI135346-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nosocomial pneumonia is a leading cause of critical illness and mortality among seriously injured trauma patients. However, the link between injury and the development of nosocomial pneumonia is still not well recognized. Our work strongly suggests that mitochondrial damage-associated molecular patterns (mtDAMPs), especially mitochondrial formyl peptides (mtFPs) released by tissue injury, play a significant role in developing nosocomial pneumonia after a serious injury. Polymorphonuclear leukocytes (neutrophils, PMN) migrate toward the injury site by detecting mtFPs through formyl peptide receptor 1 (FPR1) to fight\/contain bacterial infection and clean up debris. Activation of FPR1 by mtFPs enables PMN to reach the injury site; however, at the same time it leads to homo- and heterologous desensitization\/internalization of chemokine receptors. Thus, PMN are not responsive to secondary infections, including those from bacteria-infected lungs. This may enable a progression of bacterial growth in the lungs and nosocomial pneumonia. We propose that the intratracheal application of exogenously isolated PMN may prevent pneumonia coupled with a serious injury.<\/jats:p>","DOI":"10.3390\/ijms24087627","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T03:01:48Z","timestamp":1682046108000},"page":"7627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Can Neutrophils Prevent Nosocomial Pneumonia after Serious Injury?"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1593-5175","authenticated-orcid":false,"given":"Krist\u00edna","family":"Mac\u00e1kov\u00e1","sequence":"first","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center\/Harvard Medical School, Boston, MA 02215, USA"},{"name":"Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elzbieta","family":"Kaczmarek","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center\/Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6033-1122","authenticated-orcid":false,"given":"Kiyoshi","family":"Itagaki","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center\/Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1007\/BF01690545","article-title":"Incidence and risk factors of pneumonia acquired in intensive care units. Results from a multicenter prospective study on 996 patients. European Cooperative Group on Nosocomial Pneumonia","volume":"19","author":"Chevret","year":"1993","journal-title":"Intensive Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1086\/501655","article-title":"Screening high-risk patients for methicillin-resistant Staphylococcus aureus on admission to the hospital: Is it cost effective?","volume":"20","author":"Papia","year":"1999","journal-title":"Infect. Control Hosp. Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1097\/00005373-199911000-00018","article-title":"Infection in hospitalized trauma patients: Incidence, risk factors, and complications","volume":"47","author":"Papia","year":"1999","journal-title":"J. Trauma"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1177\/000313489906501019","article-title":"Nosocomial infections in the surgical intensive care unit: A difference between trauma and surgical patients","volume":"65","author":"Wallace","year":"1999","journal-title":"Am. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kozka, M., Sega, A., Wojnar-Gruszka, K., Tarnawska, A., and Gniadek, A. (2020). Risk Factors of Pneumonia Associated with Mechanical Ventilation. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17020656"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/0014-4894(76)90127-2","article-title":"Genetic and evolutionary consequences of symbiosis","volume":"39","author":"Margulis","year":"1976","journal-title":"Exp. Parasitol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e123","DOI":"10.1097\/CCM.0000000000004094","article-title":"Formyl Peptide Receptor-1 Blockade Prevents Receptor Regulation by Mitochondrial Danger-Associated Molecular Patterns and Preserves Neutrophil Function After Trauma","volume":"48","author":"Itagaki","year":"2020","journal-title":"Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Raoof, M., Zhang, Q., Itagaki, K., and Hauser, C.J. (2010). Mitochondrial peptides are potent immune activators that activate human neutrophils via FPR-1. J. Trauma, 68.","DOI":"10.1097\/TA.0b013e3181dcd28d"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sun, S., Sursal, T., Adibnia, Y., Zhao, C., Zheng, Y., Li, H., Otterbein, L.E., Hauser, C.J., and Itagaki, K. (2013). Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059989"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/SHK.0b013e318276f4ca","article-title":"Plasma bacterial and mitochondrial DNA distinguish bacterial sepsis from sterile systemic inflammatory response syndrome and quantify inflammatory tissue injury in nonhuman primates","volume":"39","author":"Sursal","year":"2013","journal-title":"Shock"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nature08780","article-title":"Circulating mitochondrial DAMPs cause inflammatory responses to injury","volume":"464","author":"Zhang","year":"2010","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1097\/TA.0000000000000220","article-title":"Mitochondrial damage-associated molecular patterns released by abdominal trauma suppress pulmonary immune responses","volume":"76","author":"Zhao","year":"2014","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1097\/TA.0000000000001971","article-title":"A subset of five human mitochondrial formyl peptides mimics bacterial peptides and functionally deactivates human neutrophils","volume":"85","author":"Kaczmarek","year":"2018","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1097\/TA.0000000000001413","article-title":"Intratracheal instillation of neutrophils rescues bacterial overgrowth initiated by trauma damage-associated molecular patterns","volume":"82","author":"Itagaki","year":"2017","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1164\/rccm.200307-917OC","article-title":"Prospective study of neutrophil chemokine responses in trauma patients at risk for pneumonia","volume":"171","author":"Tarlowe","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.4049\/jimmunol.171.4.2066","article-title":"Inflammatory chemoreceptor cross-talk suppresses leukotriene B4 receptor 1-mediated neutrophil calcium mobilization and chemotaxis after trauma","volume":"171","author":"Tarlowe","year":"2003","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1097\/00000542-200402000-00009","article-title":"Early onset pneumonia: Risk factors and consequences in head trauma patients","volume":"100","author":"Bronchard","year":"2004","journal-title":"Anesthesiology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Feng, X., Maze, M., Koch, L.G., Britton, S.L., and Hellman, J. (2015). Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0126906"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100785","DOI":"10.1016\/j.accpm.2020.01.012","article-title":"Risk factors for ventilator-associated pneumonia due to Staphylococcus aureus in patients with severe brain injury: A multicentre retrospective cohort study","volume":"40","author":"Launey","year":"2021","journal-title":"Anaesth. Crit. Care Pain Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1378\/chest.102.2.525","article-title":"Nosocomial respiratory tract infections in multiple trauma patients. Influence of level of consciousness with implications for therapy","volume":"102","author":"Rello","year":"1992","journal-title":"Chest"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S379","DOI":"10.1038\/sj.bjp.0707604","article-title":"Agonist-selective mechanisms of GPCR desensitization","volume":"153","author":"Kelly","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/nrmicro2200","article-title":"Waves of resistance: Staphylococcus aureus in the antibiotic era","volume":"7","author":"Chambers","year":"2009","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJM199808203390806","article-title":"Staphylococcus aureus infections","volume":"339","author":"Lowy","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1016\/j.jcyt.2017.08.012","article-title":"Granulocyte transfusions: A concise review for practitioners","volume":"19","year":"2017","journal-title":"Cytotherapy"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1016\/j.injury.2014.06.021","article-title":"The impact of trauma on neutrophil function","volume":"45","author":"Hazeldine","year":"2014","journal-title":"Injury"},{"key":"ref_26","first-page":"CD005339","article-title":"Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction","volume":"4","author":"Estcourt","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.injury.2020.10.095","article-title":"Effectiveness and safety of whole blood compared to balanced blood components in resuscitation of hemorrhaging trauma patients-A systematic review","volume":"52","author":"Malkin","year":"2021","journal-title":"Injury"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1084\/jem.20111354","article-title":"A genomic storm in critically injured humans","volume":"208","author":"Xiao","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S195","DOI":"10.1097\/01.CCM.0000057843.47705.E8","article-title":"Neutrophils and acute lung injury","volume":"31","author":"Abraham","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_31","first-page":"450","article-title":"Leukocytosis as prognostic indicator of major injury","volume":"11","author":"Paladino","year":"2010","journal-title":"West. J. Emerg. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1097\/SHK.0000000000000038","article-title":"Prehospital hypertonic saline resuscitation attenuates the activation and promotes apoptosis of neutrophils in patients with severe traumatic brain injury","volume":"40","author":"Junger","year":"2013","journal-title":"Shock"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1097\/SHK.0b013e3182635aca","article-title":"Resuscitation of traumatic hemorrhagic shock patients with hypertonic saline-without dextran-inhibits neutrophil and endothelial cell activation","volume":"38","author":"Junger","year":"2012","journal-title":"Shock"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.apmr.2012.09.015","article-title":"Phagocytic and oxidative burst activity of neutrophils in patients with spinal cord injury","volume":"94","author":"Kanyilmaz","year":"2013","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1128\/IAI.01298-10","article-title":"Enhancement of neutrophil function by interleukin-18 therapy protects burn-injured mice from methicillin-resistant Staphylococcus aureus","volume":"79","author":"Kinoshita","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2270","DOI":"10.1096\/fj.12-219519","article-title":"Resolvin D2 restores neutrophil directionality and improves survival after burns","volume":"27","author":"Kurihara","year":"2013","journal-title":"FASEB J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Liao, Y., Liu, P., Guo, F., Zhang, Z.Y., and Zhang, Z. (2013). Oxidative burst of circulating neutrophils following traumatic brain injury in human. PLoS ONE, 8.","DOI":"10.1371\/annotation\/73ce45d3-4478-4c06-a4d2-3274b6222bae"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.stem.2019.02.005","article-title":"Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility","volume":"24","author":"Xu","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4062","DOI":"10.4049\/jimmunol.134.6.4062","article-title":"Osmotic stress and the freeze-thaw cycle cause shedding of Fc and C3b receptors by human polymorphonuclear leukocytes","volume":"134","author":"Takahashi","year":"1985","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"18","DOI":"10.5581\/1516-8484.20130009","article-title":"Neutropenic patients and their infectious complications at a University Hospital","volume":"35","author":"Lima","year":"2013","journal-title":"Rev. Bras. Hematol. Hemoter."},{"key":"ref_41","first-page":"825","article-title":"Management of neutropenia in cancer patients","volume":"10","author":"Lustberg","year":"2012","journal-title":"Clin. Adv. Hematol. Oncol."},{"key":"ref_42","unstructured":"Boxer, L.A. (2006). Severe congenital neutropenia: Genetics and pathogenesis. Trans. Am. Clin. Climatol. Assoc., 117."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1182\/blood-2013-08-519520","article-title":"Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: Toward targeted treatments for immunosenescence","volume":"123","author":"Sapey","year":"2014","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1097\/SHK.0000000000001691","article-title":"Direct airway instillation of neutrophils overcomes chemotactic deficits induced by injury","volume":"56","author":"Zhang","year":"2021","journal-title":"Shock"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1097\/TA.0000000000003461","article-title":"Plasma and wound fluids from trauma patients suppress neutrophil extracellular respiratory burst","volume":"92","author":"Kim","year":"2022","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.tim.2011.11.002","article-title":"The pig: A model for human infectious diseases","volume":"20","author":"Meurens","year":"2012","journal-title":"Trends Microbiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1165\/rcmb.2013-0453TR","article-title":"Anatomy and bronchoscopy of the porcine lung. A model for translational respiratory medicine","volume":"51","author":"Judge","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1126\/science.aam9690","article-title":"Visualizing the function and fate of neutrophils in sterile injury and repair","volume":"358","author":"Wang","year":"2017","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4063","DOI":"10.4049\/jimmunol.168.8.4063","article-title":"Store-operated calcium entry in human neutrophils reflects multiple contributions from independently regulated pathways","volume":"168","author":"Itagaki","year":"2002","journal-title":"J. Immunol."},{"key":"ref_50","first-page":"e50586","article-title":"Isolation, purification and labeling of mouse bone marrow neutrophils for functional studies and adoptive transfer experiments","volume":"77","author":"Swamydas","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1089\/ars.2021.0052","article-title":"Role of Mitochondria-Derived Danger Signals Released after Injury in Systemic Inflammation and Sepsis","volume":"35","author":"Itagaki","year":"2021","journal-title":"Antioxid. Redox Signal."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7627\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:20:22Z","timestamp":1760124022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,21]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24087627"],"URL":"https:\/\/doi.org\/10.3390\/ijms24087627","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,21]]}}}