Charles C. Caldwell, Ph.D.

Research Interests

A key aspect of the high mortality associated with burn patients in the ICU is the inappropriate immune response to infection. The process of inflammation is instrumental to an organism’s response to invading microorganisms or repair of damaged tissues. This process is initiated by components of the innate immune system and is tempered by a number of regulatory mechanisms. If this hyper-inflammatory process is prolonged and/or exaggerated, significant inflammatory tissue and organ damage may ensue. In contrast, suppression of the immune response prior to complete pathogen eradication can lead to bacterial overgrowth and organ failure. As such, our lab has 3 interlocking research interests: 1) elucidation of underlying mechanisms that mediate inflammation during infections, and 2) intervention with molecular analogs to alter the immune response and eradicate the infection.

Biography

2003-09 Assistant Professor, Surgery Dept, University of Cincinnati, OH
2003- Associate, Research Division, Shriner’s Burn Institute, Cincinnati, OH
2004- Faculty, Immunobiology, Cincinnati Children’s Research Hospital, OH
2009-14 Associate Professor (tenured), Surgery Dept, University of Cincinnati, OH
2013- Director, Division of Research, Surgery Dept, University of Cincinnati, OH
2014- Professor (tenured), Department of Surgery, University of Cincinnati, OH

Education and Training

University of California, San Diego B.A. 1987-1991 Chemistry
San Diego State University Ph.D. 1992-1998 Biochemistry
Laboratory of Immunology, NIAID, NIH Post-doc 1998-2003 Immunology

Publications:

2017 (3)
1. Rice TC, Armocida SM, Kuethe JW, Midura EF, Jain A, Hildeman DA, Healy DP, Gulbins E, Caldwell CC. Burn injury influences the T cell homeostasis in a butyrate-acid sphingomyelinase dependent manner. Cell Immunol. 2016 Dec 26. PMID: 28063598

2. Johnson BL 3rd, Midura EF, Prakash PS, Rice TC, Kunz N, Kalies K, Caldwell CC. Neutrophil derived microparticles increase mortality and the counter-inflammatory response in a murine model of sepsis. BBA – Molecular Basis of Disease (2017). In press, PMID: 28108420

3. Kunz N, Xia BT, Kalies KU, Klinger M, Gemoll T, Habermann JK, Whitacre BE, Seitz AP, Kalies K, Caldwell CC. Cell-derived nanoparticles are endogenous modulators of sepsis with therapeutic potential. Shock. Accepted 23 Jan 2017 PMID: 28230708

2016 (7)
1. Rice TC, Seitz AP, Edwards MJ, Gulbins E, Caldwell CC. Sphingosine rescues burn-injured mice from pulmonary Pseudomonas aeruginosa infection. J Leukoc Biol. 2016. PubMed PMID: 27418352.

2. Midura EF, Prakash PS, Johnson BL, 3rd, Rice TC, Kunz N, Caldwell CC. Impact of caspase-8 and PKA in regulating neutrophil-derived microparticle generation. Biochem Biophys Res Commun. 2016;469(4):917-22. PubMed PMID: 26707875.

3. Midura EF, Kuethe JW, Rice TC, Veile R, England LG, Friend LA, Caldwell CC, Goodman MD. Impact of Platelets and Platelet-Derived Microparticles on Hypercoagulability Following Burn Injury. Shock. 2016;45(1):82-7. PubMed PMID: 26529651.

4. Kuethe JW, Armocida SM, Midura EF, Rice TC, Hildeman DA, Healy DP, Caldwell CC. Fecal Microbiota Transplant Restores Mucosal Integrity in a Murine Model of Burn Injury. Shock. 2016;45(6):647-52. PubMed PMID: 26682948.

5. Johnson BL, 3rd, Rice TC, Xia BT, Boone KI, Green EA, Gulbins E, Caldwell CC. Amitriptyline Usage Exacerbates the Immune Suppression Following Burn Injury. Shock. 2016. PubMed PMID: 27172154.

6. Hoehn RS, Jernigan PL, Japtok L, Chang AL, Midura EF, Caldwell CC, Kleuser B, Lentsch AB, Edwards MJ, Gulbins E, Pritts TA. Acid Sphingomyelinase Inhibition in Stored Erythrocytes Reduces Transfusion-Associated Lung Inflammation. Ann Surg. 2016. PubMed PMID: 26915288.

7. Hoehn RS, Jernigan PL, Chang AL, Edwards MJ, Caldwell CC, Gulbins E, Pritts TA. Acid Sphingomyelinase Inhibition Prevents Hemolysis During Erythrocyte Storage. Cell Physiol Biochem. 2016;39(1):331-40. PubMed PMID: 27352097.

2015 (5)
1. Kuethe JW, Midura EF, Rice TC, Caldwell CC. Peritoneal wash contents used to predict mortality in a murine sepsis model. J Surg Res. Nov 2015. J Surg Res 199(1) 211-9 PubMed PMID: 26049288.

2. Midura EF, Jernigan PL, Kuethe JW, Friend LA, Veile R, Makley AT, Caldwell CC, Goodman MD. Microparticles impact coagulation after traumatic brain injury. J Surg Res. 2015 Jul;197(1):25-31. PubMed PMID: 25846728.

3. Siegl D, Midura EF, Annecke T, Conzen P, Caldwell CC, Tschoep J. The effect of ghrelin upon the early immune response in lean and obese mice during sepsis. PLoS One. 2015 Apr 6;10(4):e0122211.. eCollection. 2015. PubMed PMID: 25844479.

4. Wilson GC, Freeman CM, Kuethe JW, Quillin RC 3rd, Nojima H, Schuster R, Blanchard J, Edwards MJ, Lentsch AB. CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice. Am J Physiol Gastrointest Liver Physiol. 2015 Apr 15;308(8):G702-9. PubMed PMID: 25721302;

5. Wang, X.,Gu, H., Qin, D., Yang, L., Huang, W., Essandoh, K., Wang, Y., Caldwell, C.C., Peng, T., Zingarelli, B., Fan, G.-C. Exosomal MIR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis. Scientific Reports, 8 Sep 2015, Vol 5:

2014 (9)
1. Siegl D, Annecke T, Johnson BL 3rd, Schlag C, Martignoni A, Huber N, Conzen P, Caldwell CC, Tschöp J. Obesity-induced Hyperleptinemia Improves Survival and Immune Response in a Murine Model of Sepsis. (2014) Anesthesiology. 121 (1) 98-114, PMID: 24595112

2. Wang X, Huang W, Yang Y, Wang Y, Peng T, Chang J, Caldwell CC, Zingarelli B, Fan GC. Loss of duplexmiR-223 (5p and 3p) aggravates myocardial depression and mortality in polymicrobial sepsis. (2014) Biochim Biophys Acta. 1842(5): 701-711, PMID: 24486439

3. C Lehmann, I Burkovskiy, J Kuethe, J Zhou, CC Caldwell, MEM Kelly. Inhibition of the cannabinoid 2 receptor in CNS-injury induced immunodeficiency syndrome. (2014) Medical Hypotheses, Jun; 82(6):736-9, PMID 24702836

4. Christian Lehmann, Nivin Sharawi, Nadia Al-Banna, Nathan Corbett, Joshua W. Kuethe, Charles C. Caldwell. Novel approaches to the development of anti-sepsis drugs (2014), Expert Opinion On Drug Discover. 9 (5) 523-31, PMID: 24697209

5. Sung Yang, M.D., David Stepien, Ph.D., Dennis Hanseman, Ph.D., Bryce Robinson, M.D., Michael D. Goodman, M.D., Timothy A. Pritts, M.D., Ph.D., Charles C. Caldwell, Ph.D., Daniel G. Remick, M.D., Alex B. Lentsch, Ph.D. Substance P mediates reduced pneumonia rates after traumatic brain injury (2014) Critical Care Medicine, In Press

6. Kuethe, JW, Prakash, PS, Midura, EF, Johnson, BL 3rd, Kasten, KR,Caldwell, CC. Thymic stromal lymphopoietin mediates the host response and increases mortality during sepsis. (2014) J. Surg. Res. PMID: 24990542, [Epub ahead of print]

7. Nanna Siegmann, David Worbs, Frauke Effinger, Tobias Bormann, Madlen Gebhardt, Martina Ulrich, Fredrik Wermeling, Eva Müller-Hermelink, Tilo Biedermann, Mike Tighe, Michael J. Edwards, Charles Caldwell, Elizabeth Leadbetter, Mikael C. I. Karlsson, Katrin Anne Becker, Erich Gulbins, Gerd Döring. Invariant natural killer T (iNKT) cells prevent autoimmunity, but induce pulmonary inflammation in cystic fibrosis. (2014). Cellular Physiology and Biochemistry. 34 (1) 56-70 PMID 24977481

8) Freeman CM, Quillin RC, Wilson GC, Nojima H, Johnson BL, Sutton JM, Schuster RM, Blanchard J, Edwards MJ, Caldwell CC, Lentsch AB. “Characterization of microparticles after hepatic ischemia-reperfusion injury.” Plos One (2014) 9(5) e97945, PMID: 24879335

9) Johnson BL, Kuethe JW, Caldwell CC. Neutrophil Derived Microvesicles: Emerging Role of a Key Mediator to the Immune Response.” (2014) Endocr Metab Immune Disord Drug Targets, [Epub ahead of print] PMID: 25051983

2013 (2)
1. Van Sweringen HL, Sakai N, Quillin RC, Bailey J, Schuster R, Blanchard J, Goetzman H, Caldwell CC, Edwards MJ, Lentsch AB. Roles of hepatocyte and myeloid CXC chemokine receptor-2 in liver recovery and regeneration after ischemia/reperfusion. (2013) Hepatology. Hepatology 57(1): 331-8. PMID: 22961770

2. Johnson, BL, Goetzman, HS, Prakash, PS, Caldwell, CC. Mechanisms Underlying Mouse TNF-α Stimulated Neutrophil Derived Microparticle Generation. (2013) Biochem Biophys Res Commun, 437(4): 591-6. PMID: 23850678

2012 (5)
1. Standage, SW, Caldwell, CC, Zingarelli, B, Wong, HR. Reduced PPAR α Expression is Associated with Decreased Survival and Increased Tissue Bacterial Load in Sepsis, Shock. 2012, Feb; 37(2) 164-9. PMID: 22089192

2. Belizaire RM, Prakash PS, Richter JR, Robinson BR, Edwards MJ, Caldwell CC, Lentsch AB, Pritts TA. Microparticles from Stored Red Blood Cells Activate Neutrophils and Cause Lung Injury after Hemorrhage and Resuscitation. J Am Coll Surg. 2012 Feb. PMID: 22342784

3. Prakash, PS, Caldwell, CC, Pritts, TA, Lentsch, AB, Robinson, BR. Human microparticles generated during sepsis in critically ill patients are neutrophil-derived and modulate the immune response. J Trauma Acute Care Surg. 73 (2): 401-7. PMID: 22846946

4.Jacqueline Unsinger, Carey-Ann Burnham, Jacquelyn McDonough, Michel Morre, Priya S. Prakash, Charles C. Caldwell, W. Michael Dunne, Richard S. Hotchkiss, IL-7 Ameliorates Immune Dysfunction and Improves Survival in a Two-Hit Model of Fungal Sepsis. (2012) J. Infect. Dis. 206 (4) 606-16. PMID: 22693226

5. Nowak, J., Harmon, K, Caldwell, CC, Wong, HR. Prophylactic zinc supplementation reduces bacterial load and improves survival in a murine model of sepsis. (2012) Pediatr Crit Care Med. 13 (5) e323-9 PMID: 22760431

2011 (2)
1. Clarke C, Kuboki S, Sakai N, Kasten KR, Tevar AD, Schuster R, Blanchard J, Caldwell CC, Edwards MJ, Lentsch AB. CXC chemokine receptor-1 is expressed by hepatocytes and regulates liver recovery after hepatic ischemia/reperfusion injury. Hepatology. 2011 Jan 53(1): 261-71 PMID: 2125417

2. Caldwell CC, Hotchkiss RS. The first step in utilizing immune-modulating therapies: immune status determination. Crit Care. 2011 Jan; 15(1):108. PMID: 2139138

2010 (10)
1: Tschöp J, Dattilo JR, Prakash PS, Kasten KR, Tschöp MH, Caldwell CC. The Leptin System: A Potential Target for Sepsis Induced Immune Suppression. Endocr Metab Immune Disord Drug Targets. 2010 Dec. 10(4) 336-47 PMID: 2092343

2: Kasten KR, Prakash PS, Unsinger J, Goetzman HS, England LG, Cave CM, Seitz AP, Mazuski CN, Zhou TT, Morre M, Hotchkiss RS, Hildeman DA, Caldwell CC. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis. Infect Immun. 2010 Nov; 78(11): 4714-22 (Featured in journal’s Spotlight) PMID: 20823197

3: Kasten KR, Tschöp J, Goetzman HS, England LG, Dattilo JR, Cave CM, Seitz AP, Hildeman DA, Caldwell CC. T-cell activation differentially mediates the host response to sepsis. Shock. 2010 Oct; 34(4): 377-83. PMID: 20610943

4: Kasten KR, Tschöp J, Adediran SG, Hildeman DA, Caldwell CC. T cells are potent early mediators of the host response to sepsis. Shock. 2010 Oct; 34(4): 327-36 PMID: 20386500

5: Adediran SG, Dauplaise DJ, Kasten KR, Tschöp J, Dattilo J, Goetzman HS, England LG, Cave CM, Robinson CT, Caldwell CC. Early infection during burn-induced inflammatory response results in increased mortality and p38-mediated neutrophil dysfunction. Am J Physiol Regul Integr Comp Physiol. 2010 Sep; 299(3): R918-25. PMID: 20592179

6: Kasten KR, Tschöp J, Tschöp MH, Caldwell CC. The cannabinoid 2 receptor as a potential therapeutic target for sepsis. Endocr Metab Immune Disord Drug Targets. 2010 Sep 10(3): 224-34. PMID: 20509835

7: Tschöp J, Nogueiras R, Haas-Lockie S, Kasten KR, Castaneda TR, Huber N, Guaniciale K, Perez-Tilve D, Habegger K, Ottaway N, Woods SC, Oldfield B, Clarke I, Chua S Jr, Farooqi IS, O’Rahilly S, Caldwell CC, Tschöp MH. CNS leptin action modulates immune response and survival in sepsis. J Neurosci. 2010 Apr; 30(17): 6036-47. PMID: 20427662

8: Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, McDonough JS, Tschoep J, Ferguson TA, McDunn JE, Morre M, Hildeman DA, Caldwell CC, Hotchkiss RS. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010 Apr; 184(7): 3768-79. PMID: 20200277

9: Kasten KR, Muenzer JT, Caldwell CC. Neutrophils are significant producers of IL-10 during sepsis. Biochem Biophys Res Commun. 2010 Feb 393(1):28-31.PMID: 20097159.

10: Kasten KR, Goetzman HS, Reid MR, Rasper AM, Adediran SG, Robinson CT, Cave CM, Solomkin JS, Lentsch AB, Johannigman JA, Caldwell CC. Divergent adaptive and innate immunological responses are observed in humans following blunt trauma. BMC Immunol. 2010 Jan 25; 11:4. (Marked as Highly accessed) PMID: 20100328

2009 (5)
1. Johannes Tschöp, André Martignoni, Maria D. Reid, Samuel G. Adediran, Jason Gardner, Greg J. Noel, Cora K. Ogle, Alice N. Neely and Charles C. Caldwell (2009) Differential immunological phenotypes are exhibited following scald and flame burns. Shock 31(2):157-163. PMID: 18650781

2. Hassett, DJ, Sutton, MD, Schurr, MJ, Herr, AB, Caldwell, CC and Matu, JO (2009) Pseudomonas aeruginosa hypoxic or anaerobic biofilm infections within cystic fibrosis airways. (2009) TRENDS in Microbiology: 17:130 PMID: 19231190

3. Satoshi Kuboki, Nozomu Sakai, Johannes Tschöp, Michael J. Edwards, Alex B. Lentsch, Charles C. Caldwell, (2009) Distinct Contributions of CD4+ T Cell Subsets in Hepatic Ischemia/Reperfusion Injury, Am J Physiol Gastrointest Liver Physiol: 296:G1054. PMID: 19264952

4. Johannes Tschöp, Kevin R. Kasten, Ruben Nogueiras, Holly S. Goetzman, Lisa G. England, Jonathan R. Dattilo, Alex B. Lentsch, Matthias H. Tschöp, and Charles C. Caldwell (2009) The cannabinoid receptor 2 is critical for the host response to sepsis, J. Immunol.: 183(1):499, PMID: 19525393

5. Charles C. Caldwell, Yi Chen, Holly S. Goetzmann, Yonghua Hao, Michael T. Borchers, Daniel J. Hassett, Lisa R. Young, Dmitri Mavrodi, Linda Thomashow, and Gee W. Lau (2009) Pseudomonas aeruginosa Exotoxin Pyocyanin Causes Cystic Fibrosis Airway Pathogenesis, Am J Pathol: 175(6):2473-88, PMID: 19893030

2008 (5)
1. Johannes Tschöp, André Martignoni, Holly S. Goetzman, Lisa G. Choi, Quan Wang, John G. Noel, Cora K. Ogle, Timothy A. Pritts, Jay A. Johannigman, Alex B. Lentsch, and Charles C. Caldwell (2008) Gamma-delta T-cells mitigate the organ injury and mortality of sepsis, J. Leuk. Bio.: 83(3):581-8 PMID: 18063696

2. André Martignoni, Johannes Tschöp, Holly S. Goetzman, Lisa G. Choi, Maria D. Reid, Jay A. Johannigman, Alex B. Lentsch, and Charles C. Caldwell (2008) CD4 expressing cells are early mediators of the innate immune system during sepsis, Shock: 29(5): 591-597 PMID:17885647

3. Charles C. Caldwell, PhD; Andre Martignoni, MD; Mike A. Leonis, MD, PhD; Hari Kumar Ondiveeran, PhD; Alison E. Fox-Robichaud, MD; Susan E. Waltz, PhD (2008) Ron receptor tyrosine kinase-dependent hepatic neutrophil recruitment and survival benefit in a murine model of bacterial peritonitis. Crit Care Med; 36(5):1585-93 PMID: 18434891

4. Ruben Nogueiras, Christelle Veyrat-Durebex, Paula M. Suchanek, Marcella Klein, Johannes Tschöp, Charles Caldwell, Stephen C. Woods, Gabor Wittmann, Masahiko Watanabe, Zsolt Liposits, Csaba Fekete, Ofer Reizes, Francoise Rohner-Jeanrenaud & Matthias H. Tschöp (2008) Peripheral, but not central, CB1 antagonism provides food intake independent metabolic benefits in diet-induced obese rats, Diabetes. 57(11): 2977-91

5. Charles C. Caldwell and Alex B Lentsch (2008) Ischemia-driven expression of CD73 confers tissue protection during liver ischemia/reperfusion. Gastroenterology, 135(5):1460-2

2007 (6)
1. Wetzel CC, Leonis MA, Dent A, Olson MA, Longmeier AM, Ney PA, Boivin GP, Kader SA, Caldwell CC, Degen SJ, Waltz SE. (2007) Short Form Ron Receptor Is Required For Normal IFN-{gamma} Production In Concanavalin A-Induced Acute Liver Injury, Am J Physiol Gastrointest Liver Physiol.: 292(1) G253-61

2. Charles C. Caldwell, Johannes Tschoep, and Alex B. Lentsch (2007) Lymphocyte Function During Hepatic Ischemia/Reperfusion Injury, J. Leuk. Bio.: 82(3):457-64

3. Julie H. Huang, L. Isabel Cárdenas-Navia, Charles C. Caldwell, Troy J. Plumb, Caius G. Radu, Paulo N. Rocha|, Tuere Wilder, Jonathan S. Bromberg, Bruce N. Cronstein, Michail Sitkovsky, Mark W. Dewhirst, and Michael L. Dustin (2007) Requirements for T lymphocyte migration in explanted lymph nodes J. Immunology: 178(12) 7747-55

4. Manfred Thiel*, Charles C. Caldwell*, Simone Kreth, Alex B. Lentsch, D. Lukashev, P. Chen, Patrick Smith, Akio Ohta, Satoshi Kuboki, and Michail Sitkovsky (2007) Targeted Deletion of HIF-1a Gene in T Cells Prevents their Inhibition in Hypoxic Inflamed Tissues and Improves Septic Mice Survival, PLoS ONE: 2(9) e853 (* Authors contributed equally to this work)

5. Pranavkumar Shivakumar, Gregg Sabla, Sujit Mohanty, Monica McNeal, Richard Ward, Keith Stringer, Charles Caldwell, Claire Chougnet, Jorge A. Bezerra (2007) Effector role of neonatal hepatic CD8+ lymphocytes in epithelial injury and autoimmunity in experimental biliary atresia, Gastroentrology: 133(1):268-77

6. Noel JG, Osterburg A, Wang Q, Guo X, Byrum D, Schewemberger S, Goetzman H, Caldwell CC, Ogle CK. (2007) Thermal injury elevates the inflammatory monocyte subpopulation in multiple compartments. Shock 28(6): 684-93

2005 (4)
1. Caldwell, C. C., T. Okaya, A. Martignoni, T. Husted, R. Schuster, and A. B. Lentsch. 2005. Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 289:G969. PMID: 16002566

2. Noel, J. G., X. Guo, D. Wells-Byrum, S. Schwemberger, C. C. Caldwell, and C. K. Ogle. 2005. Effect of thermal injury on splenic myelopoiesis. Shock 23:115.

3. Okaya, T., J. Blanchard, R. Schuster, S. Kuboki, T. Husted, C. C. Caldwell, B. Zingarelli, H. Wong, J. S. Solomkin, and A. B. Lentsch. 2005. Age-Dependent Responses To Hepatic Ischemia/Reperfusion Injury. Shock 24:421.

4. Thiel, M., A. Chouker, A. Ohta, E. Jackson, C. Caldwell, P. Smith, D. Lukashev, I. Bittmann, and M. V. Sitkovsky. 2005. Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLoS Biol 3:e174.

2003 (5)

1. Lukashev, D. E., C. C. Caldwell, P. Chen, S. G. Apasov, D. H. Margulies, and M. V. Sitkovsky. 2003. A serine/threonine phosphorylation site in the ectodomain of a T cell receptor beta chain is required for activation by superantigen. J Recept Signal Transduct Res 23:33.

2. Lukashev, D. E., P. T. Smith, C. C. Caldwell, A. Ohta, S. G. Apasov, and M. V. Sitkovsky. 2003. Analysis of A2a receptor-deficient mice reveals no significant compensatory increases in the expression of A2b, A1, and A3 adenosine receptors in lymphoid organs. Biochem Pharmacol 65:2081.

3. Olah, M. E., and C. C. Caldwell. 2003. Adenosine receptors and mammalian toll-like receptors: synergism in macrophages. Mol Interv 3:370.

4. Thiel, M., C. C. Caldwell, and M. V. Sitkovsky. 2003. The critical role of adenosine A2A receptors in downregulation of inflammation and immunity in the pathogenesis of infectious diseases. Microbes Infect 5:515.

5. Wen, L. T., C. C. Caldwell, and A. F. Knowles. 2003. Poly (ADP-ribose) polymerase activation and changes in Bax protein expression associated with extracellular ATP-mediated apoptosis in human embryonic kidney 293-P2X7 cells. Mol Pharmacol 63:706.

Grants

Title: Mechanisms underlying CB2R regulation of myeloid cells during inflammation
Source: Shriners Hospitals for Children (Award ID: 85210-CIN)
Duration: Jan 2013 – Dec 2017
Sepsis represents a clinical syndrome resulting from the body’s systemic inflammatory response to bacterial infection. It is difficult to treat and carries high rates of morbidity and mortality. We have recently discovered that the cannabinoid 2 receptor (CB2R) plays a critical role in regulating the innate immune response. The three aims proposed in this grant application are as follows: 1) Characterize the endocannabinoid system during sepsis, 2) Define mechanisms underlying CB2R modulation of myeloid cell function during sepsis, and 3) Determine how the CB2R influences neutrophil function and recruitment. The data obtained from these studies have the potential to greatly advance our knowledge of the pathophysiology of sepsis and may identify several novel potential therapeutic targets.
Direct Funding: $185,000 / year
Role: Principal Investigator
Effort: 35%

Title: Neutrophil-derived microparticle generation and immune impact during sepsis
Source: NIH (NIGMS R01 GM100913)
Duration: Dec 2012 – Nov 2017
During sepsis, exquisite control of inflammation is necessary to execute beneficial actions (bacterial clearance) while minimizing pathogenesis. Initially, activated leukocytes participate in the anti-microbial response. During sepsis, leukocytes can undergo apoptosis or become unresponsive. In other inflammatory models, both activated and apoptotic leukocytes have been shown to be precursors to microparticles (MPs). MPs are small vesicles of heterogeneous density and composition. The role of MPs in sepsis is currently poorly characterized. Our novel preliminary data demonstrate that neutrophil-derived MPs (NDMPs) are increased during sepsis, decrease survival and can increase immune suppression. Altogether, our overarching hypothesis is that the formation of sepsis-generated MPs will significantly contribute to immune paralysis such that mortality is increased. Mechanistic underpinnings of this hypothesis will be tested in the following aims: Aim 1: Determine TLR4-associated molecular mechanisms driving NDMP formation. Aim 2: Characterize how NDMPs influence T cell activation and homeostasis. Aim 3: Elucidate mechanisms of NDMP-associated macrophage de-activation. Successful completion of these aims may lead to therapies aimed towards reversing sepsis-induced immune paralysis.
Direct Funding: NCE
Role: Principal Investigator

Title: Exploiting bioactive lipid properties to rescue burn-injured mice from lung infection
Source: Shriners Hospital for Children / 85000
Duration: Jan 2017 – Dec 2021
Infection is the most common cause of burn-related morbidity and mortality. In particular, burn-injured patients are highly susceptible to Pseudomonas aeruginosa (PA) infections as it is the single most frequently isolated bacterial pathogen. In patients with concomitant burn injury and pulmonary PA infection, mortality rates can be as high as 50%, despite antibiotic therapy. Reinforcing endogenous antimicrobial systems would circumvent this clinical problem. We will test whether inhalation of sphingosine, derivatives or acid ceramidase constitutes a novel treatment paradigm to prevent and cure pulmonary P. aeruginosa infection (bench to bed). Altogether, if our proposed aims are successful, we will further develop the novel concept of the immediate defense in upper airways by sphingosine and the permissive facilitation by ceramide to develop potential therapies to prevent and cure pneumonia in burned mice.
Direct Funding: $240,000 / year
Role: Principal Investigator
Effort: 25%

Title: The Effect of Hypobaria on Muscle Inflammation and Regeneration After Injury and Hemorrhagic Shock
Source: U.S. ARMY MEDICAL RESEARCH
Duration: Nov 2015- Oct 2019
The proposed research focuses on lower extremity muscle trauma and hemorrhagic shock, which are major battlefield injuries. The specific aims of the study are (a) To establish a combat casualty/en route care experimental model that incorporates lower extremity muscle injury and hemorrhagic shock with fluid resuscitation and simulates the hypobaria exposure of air transport from the Pacific theater to the United States. (b) To test the effect of 16-hour hypobaria exposure on leukocyte characteristics, function, and related genes responsive to muscle injury in a combat casualty/en route care experimental model. (c) To test the effect of 16-hour hypobaria exposure on muscle regenerative processes and functional properties in a combat casualty / en route care experimental model.
Direct Funding: $19,360 / year
Role: Sub-award (PI Parent Grant: St. Pierre Schneider)
Effort: 5%

Title: RED BLOOD CELL MICROPARTICLES AND LUNG INFLAMMATION AFTER HEMORRHAGE AND RESUSCITION
Source: NIH / NIGMS 1R01 GM107625
Duration: Feb 2014 – Dec 2018
In the current proposal, we hypothesize that microparticles from stored packed RBCs are pro-inflammatory in nature and promote inflammatory consequences, such as the development of lung inflammation, after resuscitation from hemorrhage. To test this hypothesis, we propose the following specific aims. Aim 1: Determine the nature of the formation and biochemical composition of microparticles during storage of pRBC units. Aim 2: Determine the molecular mechanisms of cellular activation by RBC derived microparticles. Aim 3: Determine the manner in which RBC microparticles promote multi-cellular interactions leading to organ inflammation after hemorrhage and resuscitation. The proposed studies will generate novel data concerning the role of microparticles in the inflammatory sequelae during hemorrhage and resuscitation.
Direct Funding: $200,000
Role: Co-l Investigator (PI – Timothy A. Pritts)
Effort: 5%

Title: DUPLEX MIR-223 AND EXOSOMES IN SEPSIS
Source: NIH / NIGMS 1 R01 GM112930-01
Duration: 1/1/2015 – 12/31/2018
Cardiovascular dysfunction is a major contributor to sepsis-induced death in critically ill patients. We hypothesize that global elevation of duplex miR-223 limits sepsis-induced cardiac dysfunction and mortality and loss of duplex miR-223 contributes to septic exosome-triggered cardiac dysfunction. These will be tested by three specific aims: 1) Using a transgenic mouse model, we will test whether global elevation of duplex miR-223 attenuates sepsis-induced myocardial depression and mortality; 2) Utilizing duplex miR-223-null exosomes and septic exosomes isolated from the blood of miR-223-knockout mice and CLP-operated mice to test whether septic exosome-mediated cardiac dysfunction and mortality is ascribed to the reduction of duplex miR-223; and 3) We will use bone marrow-derived mesenchymal stem cells (MSCs) as a source of miR-223-exosomes to determine the therapeutic effects of duplex-miR-223- engineered exosomes on sepsis-induced cardiac dysfunction and mortality.
Direct Funding: $190,000 / year
Role: Co-Investigator (PI – Fan)
Effort: 3%

Title: Epoxyeicosatrienoic Acids: Therapeutic Potential in Skin Grafting and Burns
Source: Shriners Hospital for Children
Duration: 1/1/2017 – 12/31/2020
Treatment of large burns is challenging due to complex disruptions of systemic homeostasis. Burns can cause profound immune disruption and hyperinflammatory responses that contribute to increased susceptibility to infection, remote organ injury and death. In burn survivors, delayed burn wound closure and excessive inflammation may lead to hypertrophic scarring, impacting long-term functional outcome. Wound closure can be challenging in patients with large burns due to insufficient uninjured skin for autografting. Open burn wounds serve as a portal for entry of microorganisms that can contribute to infection and pneumonia, which are among the leading causes of death in burn patients. Although previous studies showed the feasibility of healing large excised burns with engineered skin substitutes (ESS), ESS exhibit limitations, such as lack of a vascular plexus, that can delay vascularization and reduce engraftment. ESS are also limited due to absent or irregular pigmentation. Melanocytes in ESS can provide pigmentation, although hyperpigmentation may result. Hyperpigmentation of healed burns is relatively common and has been associated with inflammation. These studies may lead to novel strategies to regulate post-burn inflammation and its pathological consequences and improve healing of autograft and engineered skin.
Direct Funding: $250,000 / year
Role: Co-Investigator (PI – Supp)
Effort: 7%

Contact

Charles C. Caldwell, Ph.D.
Professor
Research
[email protected]

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