Teresa C Rice1, Amanda M Pugh1, Brent T Xia1, Aaron P Seitz1, Brynne E Whitacre1, Erich Gulbins2, Charles C Caldwell3. 1. Division of Research, Department of Surgery, University of Cincinnati, Cincinnati, OH. 2. Division of Research, Department of Surgery, University of Cincinnati, Cincinnati, OH; Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany. 3. Division of Research, Department of Surgery, University of Cincinnati, Cincinnati, OH. Electronic address: charles.caldwell@uc.edu.
Abstract
BACKGROUND: Pseudomonas aeruginosa is a major cause of morbidity and mortality among burn patients, despite antibiotic therapy. There is a need to identify innate immune defenses that prevent P aeruginosa infection in injured adults in an effort to find therapeutic alternatives to antibiotics. Here, we tested our hypothesis that microvesicles (MVs) in bronchoalveolar (BAL) fluid have a role in the immunity of the lung in response to pathogens. STUDY DESIGN: Microvesicles were isolated from murine BAL fluid, quantified using Nanoparticle Tracking Analysis, and injected into burn-injured mice before P aeruginosa infection. Survival was assessed and BAL bacterial loads enumerated. Neutrophil number and interleukin 6 activity were determined. Lungs were harvested and sphingosine (SPH) content analyzed via immunohistochemistry. Antimicrobial effects of MVs and SPH-enriched MVs were assessed in an in vitro assay. RESULTS: Burn-injured mice have reduced BAL MV number and SPH content compared with sham. When BAL MVs from healthy mice are administered to injured mice, survival and bacterial clearance are improved robustly. We also observed that intranasal administration of MVs restores SPH levels after burn injury, MVs kill bacteria directly, and this bacterial killing is increased when the MVs are supplemented with SPH. CONCLUSIONS: Using a preclinical model, BAL MVs are reduced after scald injury and BAL MV restoration to injured mice improves survival and bacterial clearance. The antimicrobial mechanisms leading to improved survival include the quantity and SPH content of BAL MVs.
BACKGROUND:Pseudomonas aeruginosa is a major cause of morbidity and mortality among burn patients, despite antibiotic therapy. There is a need to identify innate immune defenses that prevent P aeruginosa infection in injured adults in an effort to find therapeutic alternatives to antibiotics. Here, we tested our hypothesis that microvesicles (MVs) in bronchoalveolar (BAL) fluid have a role in the immunity of the lung in response to pathogens. STUDY DESIGN: Microvesicles were isolated from murine BAL fluid, quantified using Nanoparticle Tracking Analysis, and injected into burn-injured mice before P aeruginosa infection. Survival was assessed and BAL bacterial loads enumerated. Neutrophil number and interleukin 6 activity were determined. Lungs were harvested and sphingosine (SPH) content analyzed via immunohistochemistry. Antimicrobial effects of MVs and SPH-enriched MVs were assessed in an in vitro assay. RESULTS: Burn-injured mice have reduced BAL MV number and SPH content compared with sham. When BAL MVs from healthy mice are administered to injured mice, survival and bacterial clearance are improved robustly. We also observed that intranasal administration of MVs restores SPH levels after burn injury, MVs kill bacteria directly, and this bacterial killing is increased when the MVs are supplemented with SPH. CONCLUSIONS: Using a preclinical model, BAL MVs are reduced after scald injury and BAL MV restoration to injured mice improves survival and bacterial clearance. The antimicrobial mechanisms leading to improved survival include the quantity and SPH content of BAL MVs.
Authors: María Yáñez-Mó; Pia R-M Siljander; Zoraida Andreu; Apolonija Bedina Zavec; Francesc E Borràs; Edit I Buzas; Krisztina Buzas; Enriqueta Casal; Francesco Cappello; Joana Carvalho; Eva Colás; Anabela Cordeiro-da Silva; Stefano Fais; Juan M Falcon-Perez; Irene M Ghobrial; Bernd Giebel; Mario Gimona; Michael Graner; Ihsan Gursel; Mayda Gursel; Niels H H Heegaard; An Hendrix; Peter Kierulf; Katsutoshi Kokubun; Maja Kosanovic; Veronika Kralj-Iglic; Eva-Maria Krämer-Albers; Saara Laitinen; Cecilia Lässer; Thomas Lener; Erzsébet Ligeti; Aija Linē; Georg Lipps; Alicia Llorente; Jan Lötvall; Mateja Manček-Keber; Antonio Marcilla; Maria Mittelbrunn; Irina Nazarenko; Esther N M Nolte-'t Hoen; Tuula A Nyman; Lorraine O'Driscoll; Mireia Olivan; Carla Oliveira; Éva Pállinger; Hernando A Del Portillo; Jaume Reventós; Marina Rigau; Eva Rohde; Marei Sammar; Francisco Sánchez-Madrid; N Santarém; Katharina Schallmoser; Marie Stampe Ostenfeld; Willem Stoorvogel; Roman Stukelj; Susanne G Van der Grein; M Helena Vasconcelos; Marca H M Wauben; Olivier De Wever Journal: J Extracell Vesicles Date: 2015-05-14
Authors: Teresa C Rice; Aaron P Seitz; Michael J Edwards; Erich Gulbins; Charles C Caldwell Journal: J Leukoc Biol Date: 2016-07-14 Impact factor: 4.962
Authors: Meng Liu; Hui Li; Chun Xue Xue; Li Gu; Jiu Xin Qu; Xiao Min Yu; Yi Min Wang; Ying Mei Liu; Bin Cao Journal: Clin Respir J Date: 2017-02-15 Impact factor: 2.570
Authors: Elzbieta Pluskota; Neil M Woody; Dorota Szpak; Christie M Ballantyne; Dmitry A Soloviev; Daniel I Simon; Edward F Plow Journal: Blood Date: 2008-05-28 Impact factor: 22.113
Authors: Johannes Tschöp; André Martignoni; Maria D Reid; Samuel G Adediran; Jason Gardner; Greg J Noel; Cora K Ogle; Alice N Neely; Charles C Caldwell Journal: Shock Date: 2009-02 Impact factor: 3.454
Authors: Lacy E Lowry; Maryanne C Herzig; Barbara A Christy; Richard Schäfer; Shibani Pati; Andrew P Cap; James A Bynum Journal: Stem Cell Rev Rep Date: 2021-01-08 Impact factor: 6.692
Authors: Micah L Willis; Cressida Mahung; Shannon M Wallet; Alexandra Barnett; Bruce A Cairns; Leon G Coleman; Robert Maile Journal: J Leukoc Biol Date: 2021-08-03 Impact factor: 4.962