About

Nathan J. Klingensmith, MD, is an Assistant Professor of Surgery at the Hospital of the University of Pennsylvania. He is an active surgeon affiliated with Penn Presbyterian Medical Center, the Corporal Michael J. Crescenz Veterans Affairs Medical Center, and Pennsylvania Hospital in Philadelphia. Dr. Klingensmith serves as the Director of Education for the Division of Traumatology, Surgical Critical Care, and Emergency Surgery within the Department of Surgery at the University of Pennsylvania. His research expertise includes sepsis, microbiome, red blood cells, and DNA, with a focus on understanding inflammatory responses and host responses during polymicrobial sepsis. His work involves investigating the role of red blood cell DNA capture and delivery in driving host responses, as well as exploring toll-like receptor expression on human red blood cells. Dr. Klingensmith has contributed to numerous publications in the field of trauma and critical care, emphasizing the molecular mechanisms underlying sepsis and inflammation.

Research topics

• Medicine
• Surgery
• Immunology
• Biology
• Internal medicine

Selected publications

• The Role of High Dose Continuous Renal Replacement Therapy in Acute Liver Failure Following High Grade Liver Trauma

  American Journal of Transplantation · 2025-08-01

  articleOpen access
  PublisherOA PDFDOI

• Human red blood cells express the RNA sensor TLR7

  Scientific Reports · 2024-07-09 · 8 citations

  articleOpen access

  Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs.

  PublisherOA PDFDOI

• CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice

  ImmunoHorizons · 2024-01-01 · 4 citations

  articleOpen access

  Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.

  PublisherOA PDFDOI

• Red blood cells capture and deliver bacterial DNA to drive host responses during polymicrobial sepsis

  Journal of Clinical Investigation · 2024-12-12 · 7 citations

  articleOpen access

  Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro, and bacterial DNA-induced (bDNA-induced) macrophage activation was augmented by WT, but not Tlr9-deleted, RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bDNA was elevated in WT mice but not in erythroid Tlr9-deleted mice. Plasma cytokine analysis in these mice revealed distinct sepsis clusters characterized by persistent hypothermia and hyperinflammation in the most severely affected mice. RBC Tlr9 deletion attenuated plasma and tissue IL-6 production in the most severely affected group. Parallel findings in humans confirmed that RBCs from patients with sepsis harbored more bDNA than did RBCs from healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.

  PublisherOA PDFDOI

• Red Blood Cell DNA Capture and Delivery Drives Host Responses During Polymicrobial Sepsis

  Research Square · 2024-04-23

  preprintOpen access
  PublisherOA PDFDOI

• Publisher Correction: European society for trauma and emergency surgery member-identified research priorities in emergency surgery: a roadmap for future clinical research opportunities

  European Journal of Trauma and Emergency Surgery · 2024-08-22

  erratumOpen access

  Publisher Correction: European Journal of Trauma and Emergency Surgery (2024) 50:367-382 https://doi.org/10.1007/s00068-023-02441-3 The original version of this article, published on 27 February 2024, unfortunately contained a mistake. In this article Ingo Marzi should have been denoted as the second corresponding author.

  PublisherOA PDFDOI

• Human Red Blood Cells Express Toll-like Receptor 7 and Bind Single Stranded RNA

  2024-04-30

  article
  PublisherDOI

• European society for trauma and emergency surgery member-identified research priorities in emergency surgery: a roadmap for future clinical research opportunities

  European Journal of Trauma and Emergency Surgery · 2024-02-27 · 6 citations

  reviewOpen access

  BACKGROUND: European Society for Trauma and Emergency Surgery (ESTES) is the European community of clinicians providing care to the injured and critically ill surgical patient. ESTES has several interlinked missions - (1) the promotion of optimal emergency surgical care through networked advocacy, (2) promulgation of relevant clinical cognitive and technical skills, and (3) the advancement of scientific inquiry that closes knowledge gaps, iteratively improves upon surgical and perioperative practice, and guides decision-making rooted in scientific evidence. Faced with multitudinous opportunities for clinical research, ESTES undertook an exercise to determine member priorities for surgical research in the short-to-medium term; these research priorities were presented to a panel of experts to inform a 'road map' narrative review which anchored these research priorities in the contemporary surgical literature. METHODS: Individual ESTES members in active emergency surgery practice were polled as a representative sample of end-users and were asked to rank potential areas of future research according to their personal perceptions of priority. Using the modified eDelphi method, an invited panel of ESTES-associated experts in academic emergency surgery then crafted a narrative review highlighting potential research priorities for the Society. RESULTS: Seventy-two responding ESTES members from 23 countries provided feedback to guide the modified eDelphi expert consensus narrative review. Experts then crafted evidence-based mini-reviews highlighting knowledge gaps and areas of interest for future clinical research in emergency surgery: timing of surgery, inter-hospital transfer, diagnostic imaging in emergency surgery, the role of minimally-invasive surgical techniques and Enhanced Recovery After Surgery (ERAS) protocols, patient-reported outcome measures, risk-stratification methods, disparities in access to care, geriatric outcomes, data registry and snapshot audit evaluations, emerging technologies interrogation, and the delivery and benchmarking of emergency surgical training. CONCLUSIONS: This manuscript presents the priorities for future clinical research in academic emergency surgery as determined by a sample of the membership of ESTES. While the precise basis for prioritization was not evident, it may be anchored in disease prevalence, controversy around aspects of current patient care, or indeed the identification of a knowledge gap. These expert-crafted evidence-based mini-reviews provide useful insights that may guide the direction of future academic emergency surgery research efforts.

  PublisherOA PDFDOI

• Burns

  2023-01-01

  book-chapter1st authorCorresponding
  PublisherDOI

• Red Blood Cell DNA Capture and Delivery Drives Host Responses During Polymicrobial Sepsis

  Research Square · 2023-04-03

  preprintOpen access
  PublisherDOI

Frequent coauthors

• Alexis M. Moren

  Salem Hospital

  338 shared

• Mark J. Seamon

  University of Pennsylvania

  338 shared

• Anthony Loria

  University of Rochester Medical Center

  338 shared

• David Skarupa

  338 shared

• Jane Keating

  Lancaster General Hospital

  338 shared

• Zoë Maher

  Temple University

  338 shared

• Michael C. Smith

  Vanderbilt University Medical Center

  338 shared

• Joanelle Bailey

  Hackensack University Medical Center

  169 shared

Awards & honors

• European Society for Trauma and Emergency Surgery member-ide…
• CTLA-4 checkpoint inhibition improves sepsis survival in alc…