The Novel MFG-E8-derived Oligopeptide, MOP3, Improves Outcomes in a Preclinical Murine Model of Neonatal Sepsis.

INTRODUCTION: Neonatal sepsis is a devastating inflammatory condition that remains a leading cause of morbidity and mortality. Milk fat globule-EGF-factor VIII (MFG-E8) is a glycoprotein that reduces inflammation, whereas extracellular cold-inducible RNA binding protein (eCIRP) worsens inflammation. This study aimed to determine the therapeutic potential of a novel MFG-E8-derived oligopeptide 3 (MOP3) designed to clear eCIRP and protect against inflammation, organ injury, and mortality in neonatal sepsis. METHODS: C57BL6 mouse pups were injected intraperitoneally with cecal slurry (CS) and treated with MOP3 (20 µg/g) or vehicle. 10 h after injection, blood, lungs, and intestines were collected for analyses, and in a 7-day experiment, pups were monitored for differences in mortality. RESULTS: MOP3 treatment protected septic pups from inflammation by reducing eCIRP, IL-6, TNFα, and LDH. MOP3 reduced lung and intestinal inflammation and injury as assessed by reductions in tissue mRNA levels of inflammatory markers, histopathologic injury, and apoptosis in lung and intestines. MOP3 also significantly improved 7-day overall survival for CS-septic mouse pups compared to vehicle (75% vs. 46%, respectively). CONCLUSION: Deriving from MFG-E8 and designed to clear eCIRP, MOP3 protects against sepsis-induced inflammation, organ injury, and mortality in a preclinical model of neonatal sepsis, implicating it as an exciting potential new therapeutic. LEVEL OF EVIDENCE: Level 1.

Impact of the COVID-19 pandemic on trauma activations at a pediatric level 1 trauma center in New York.

BACKGROUND: The disruptive effects on society and medical systems due to the coronavirus disease 2019 (COVID-19) pandemic are substantial and far-reaching. The effect of the pandemic on the quantity and quality of pediatric traumas is unclear and has a direct bearing on how scarce hospital resources should be allocated in a pandemic situation. METHODS: A retrospective review of the trauma registry was performed for trauma activations in the years 2018 through 2020 during the months of March, April, and May. Demographic and injury specific datapoints were compared across calendar years. RESULTS: There were 111, 100, and 52 trauma activations during the study interval in 2018, 2019, and 2020, respectively. There were fewer highest severity level activations in 2020 compared to 2018 and 2019 (1 vs 5 and 9; p < 0.01). The median Injury Severity Score was 5 in 2020 compared to 4 in both 2018 and 2019 (p < 0.01). More patients went directly to the operating room in 2020 compared to prior years (21.2% vs 8% and 6.1%; p < 0.01). There were fewer discharges from the emergency department (ED) (12.1% vs 36.6% and 32.7%). No increase in the number of child abuse reports and investigations was noted. There was no difference in the proportion of blunt versus penetrating trauma between years (p = 0.57). No pedestrians were struck by automobiles in 2020 compared to 12 and 14 in 2018 and 2019. However, there were a greater proportion of injuries from falls during 2020 compared to prior years. CONCLUSIONS: There were fewer trauma activations during the peak of the COVID pandemic compared to prior years. Due to the decrease in trauma volume during the peak of the pandemic, hospital resources could potentially be reallocated toward areas of greater need. LEVEL OF EVIDENCE: IV; Retrospective cohort study using historical controls.

Limiting hospital resources for acute appendicitis in children: Lessons learned from the U.S. epicenter of the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic resulted in the suspension of nonemergent surgeries throughout New York. Our tertiary care children's hospital pivoted towards a brief trial of intravenous (IV) antibiotic therapy in all patients in order to limit operating room (OR) utilization and avoid prolonged hospital stays. We describe our pandemic-based strategy for non-operative management (NOM) of appendicitis but with a limited duration of IV antibiotics. METHODS: We performed a retrospective study of children treated for acute appendicitis at our center from 3/31/2020 to 5/3/2020 during the peak of the New York pandemic. We compared appendicitis volume to similar months in prior years. We evaluated failure of NOM, length of stay, and compared characteristics of children we successfully treated with our expanded NOM protocol to previously published inclusion criteria for NOM. RESULTS: 45.5% of children (25/55) with acute appendicitis underwent NOM. Of the 30 who underwent surgery, 13 had complicated appendicitis while 17 had simple appendicitis. Three patients were COVID-positive, although none had respiratory symptoms. The majority of patients presenting with acute appendicitis (78.2%) did not meet previously published criteria for NOM. CONCLUSIONS: We treated a similar volume of children with acute appendicitis during the pandemic compared to prior years. We applied non-operative management to nearly half our patients, even as we expanded inclusion criteria for NOM to reduce OR utilization, but limited the duration of the antibiotic trial to avoid prolonged hospital stays. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: IV.

Targeting the eCIRP/TREM-1 interaction with a small molecule inhibitor improves cardiac dysfunction in neonatal sepsis.

BACKGROUND: Neonatal sepsis and the associated myocardial dysfunction remain a leading cause of infant mortality. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a ligand of triggering receptor expressed on myeloid cells-1 (TREM-1). M3 is a small CIRP-derived peptide that inhibits the eCIRP/TREM-1 interaction. We hypothesize that the eCIRP/TREM-1 interaction in cardiomyocytes contributes to sepsis-induced cardiac dysfunction in neonatal sepsis, while M3 is cardioprotective. METHODS: Serum was collected from neonates in the Neonatal Intensive Care Unit (NICU). 5-7-day old C57BL/6 mouse pups were used in this study. Primary murine neonatal cardiomyocytes were stimulated with recombinant murine (rm) CIRP with M3. TREM-1 mRNA and supernatant cytokine levels were assayed. Mitochondrial oxidative stress, ROS, and membrane potential were assayed. Neonatal mice were injected with rmCIRP and speckle-tracking echocardiography was conducted to measure cardiac strain. Sepsis was induced by i.p. cecal slurry. Mouse pups were treated with M3 or vehicle. After 16 h, echocardiography was performed followed by euthanasia for tissue analysis. A 7-day survival study was conducted. RESULTS: Serum eCIRP levels were elevated in septic human neonates. rmCIRP stimulation of cardiomyocytes increased TREM-1 gene expression. Stimulation of cardiomyocytes with rmCIRP upregulated TNF-α and IL-6 in the supernatants, while this upregulation was inhibited by M3. Stimulation of cardiomyocytes with rmCIRP resulted in a reduction in mitochondrial membrane potential (MMP) while M3 treatment returned MMP to near baseline. rmCIRP caused mitochondrial calcium overload; this was inhibited by M3. rmCIRP injection impaired longitudinal and radial cardiac strain. Sepsis resulted in cardiac dysfunction with a reduction in cardiac output and left ventricular end diastolic diameter. Both were improved by M3 treatment. Treatment with M3 attenuated serum, cardiac, and pulmonary levels of pro-inflammatory cytokines compared to vehicle-treated septic neonates. M3 dramatically increased sepsis survival. CONCLUSIONS: Inhibition of eCIRP/TREM-1 interaction with M3 is cardioprotective, decreases inflammation, and improves survival in neonatal sepsis. Trial registration Retrospectively registered.

Inhibition of a triggering receptor expressed on myeloid cells-1 (TREM-1) with an extracellular cold-inducible RNA-binding protein (eCIRP)-derived peptide protects mice from intestinal ischemia-reperfusion injury.

BACKGROUND: Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS: Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS: Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION: Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.

Pediatric Robotic Surgery.

Pediatric robotic-assisted surgery is quickly gaining traction in pediatric surgical disciplines but presents unique challenges as compared to adult robotic surgery. Small abdominal and thoracic cavities limit working space and operative indications differ from the adult population. This article describes the development of pediatric robotic-assisted surgery, discusses technical limitations and benefits, and reviews training considerations particular to robotic surgery. Applications and published outcomes of common procedures in urology, general and thoracic surgery, otolaryngology, and pediatric surgical oncology are described. Finally, costs and the anticipated future direction of pediatric robotic-assisted surgery are discussed.

Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis.

Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently discovered damage-associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation is essential. Here we identified that eCIRP is a new biologically active endogenous ligand of triggering receptor expressed on myeloid cells-1 (TREM-1), fueling inflammation in sepsis. Surface plasmon resonance revealed a strong binding affinity between eCIRP and TREM-1, and fluorescence resonance energy transfer assay confirmed eCIRP's interaction with TREM-1 in macrophages. Targeting TREM-1 by its siRNA or a decoy peptide, LP17, or by using TREM-1-/- mice dramatically reduced eCIRP-induced inflammation. We developed a potentially novel 7-aa peptide derived from human eCIRP, M3, which blocked the interaction of TREM-1 and eCIRP. M3 suppressed inflammation induced by eCIRP or agonist TREM-1 antibody cross-linking in murine macrophages or human peripheral blood monocytes. M3 also inhibited eCIRP-induced systemic inflammation and tissue injury. Treatment with M3 further protected mice from sepsis, improved acute lung injury, and increased survival. Thus, we have discovered a potentially novel TREM-1 ligand and developed a new peptide, M3, to block eCIRP-TREM-1 interaction and improve outcomes in sepsis.

EAST multicenter trial of simulation-based team training for pediatric trauma: Resuscitation task completion is highly variable during simulated traumatic brain injury resuscitation.

BACKGROUND: Best practices for benchmarking the efficacy of simulation-based training programs are not well defined. This study sought to assess feasibility of standardized data collection with multicenter implementation of simulation-based training, and to characterize variability in pediatric trauma resuscitation task completion associated with program characteristics. METHODS: A prospective multicenter observational cohort of resuscitation teams (N = 30) was used to measure task completion and teamwork during simulated resuscitation of a child with traumatic brain injury. A survey was used to measure center-specific trauma volume and simulation-based training program characteristics among participating centers. RESULTS: No task was consistently performed across all centers. Teamwork skills were associated with faster time to computed tomography notification (r = -0.51, p < 0.01). Notification of the operating room by the resuscitation team occurred more frequently in in situ simulation than in laboratory-based simulation (13/22 versus 0/8, p < 0.01). CONCLUSIONS: Multicenter implementation of a standardized pediatric trauma resuscitation simulation scenario is feasible. Standardized data collection showed wide variability in simulated resuscitation task completion.

La enfermedad pulmonar obstructiva crónica es un problema de salud / Chronic obstructive pulmonary disease is a health problem

RESUMEN La enfermedad pulmonar obstructiva crónica se caracteriza por una limitación crónica al flujo aéreo poco reversible y asociada en particular al humo de tabaco. Se trata de una enfermedad infradiagnosticada y con una elevada morbimortalidad, lo que implica un problema de salud pública de gran magnitud. Constituye la cuarta causa de muerte en los países del Caribe y se prevé que su prevalencia siga en aumento, lo que representa un elevado costo sanitario. En Cuba la enfermedad pulmonar obstructiva crónica constituye la quinta causa de muerte con una tendencia ascendente en los próximos años, por lo que es un problema de salud, del que no se excluye la provincia de Matanzas, como causa de ingresos frecuentes en sus unidades de atención al grave, las cuales en ocasiones presentan una evolución desfavorable. Entre los factores de riesgo que incrementan esta entidad se encuentran el tabaquismo y la contaminación ambiental, que aumentan la morbilidad por esta entidad con complicaciones que prolongan la estadía hospitalaria y elevan la mortalidad (AU).

SUMMARY Chronic obstructive pulmonary disease is characterized by the chronic limitation of the airflow, almost irreversible and mainly associated to tobacco smoke. It is an underdiagnosed disease with a high morbimortality, meaning a health problem of high magnitude. It is the fourth cause of death in the Caribbean countries and it is expected its prevalence will still increase, representing a high sanitary cost. In Cuba, it is the fifth cause of death with an increasing tendency in the next years, being a health problem because it causes frequent admissions in the Seriously-ill Care Units, frequently having an unfavorable evolution. The province of Matanzas is not excluded from this. Smoking and environmental pollution are among the risk factors favoring this entity, increasing this entity morbidity with complications that make hospital staying longer and mortality higher (AU).

Guías en función del trabajo independiente para estudiantes de las Ciencias Médicas / Guidelines for the independent work of Medical Sciences students

RESUMEN El hombre con su sabiduría e inteligencia ha sido capaz de crear medios de enseñanza, que no se han quedado relegados en el tiempo, los ha puesto al servicio de la educación para el logro de la formación integral de la personalidad. El nuevo siglo se ha caracterizado por un aumento del volumen de conocimientos en cualquier rama de la ciencia, necesita del trabajo independiente en la formación del estudiante, en cualquier nivel de enseñanza. El propósito orientar a los profesores un grupo de requerimientos didácticos para estructurar guías de estudio en función del trabajo independiente para estudiantes de las Ciencias Médicas. Se realizó un estudio documental del tema, mediante búsquedas en las bases de datos SciELO Cuba, SciELO Regional, Pubmed, de todo lo relacionado con el tema en el período 2017-2018. Se define como guía didáctica al instrumento digital o impreso que constituye un recurso para el aprendizaje a través del cual se concreta la acción del profesor y los estudiantes dentro del proceso docente, de forma planificada y organizada. Se declaran requerimientos didácticas para el desarrollo del proceso de enseñanza aprendizaje que complementan la forma de asimilación de los conocimientos. Las guías didácticas en función del trabajo independiente constituyen recursos que tienen el propósito de orientar metodológicamente al estudiante en su actividad independiente, al mismo tiempo que sirvan de apoyo a la dinámica del proceso docente, al guiar al alumno en su aprendizaje, al favorecer la autonomía, la relación de los conocimientos, habilidades y valores, así como la participación comunitaria como escenario para realizar el trabajo independiente (AU).

SUMMARY The man, with his wisdom and intelligence, has been able to create teaching aids that have not been forgotten through the times; they have been put in to service of teaching to achieve the comprehensive training of the personality. The new century, characterized by the increase of knowledge volume in every branch of the sciences, needs the independent work for training students of all education levels. The purpose is providing the teachers a group of didactic requirements to prepare study guidelines for the independent work of Medical Sciences students. A documental study of the theme was carried out searching all publications on the theme published in Scielo Cuba, Scielo Regional, and Pubmed in the period 2017-2018. Didactic guideline is the digital or printed document used as a resource for learning, through which the performance of the teacher and the students is fulfilled in the teaching process, in an organized and planned way, and declares didactic requirements for the development of the teaching learning process complementing the assimilation of knowledge. Didactic guidelines in function of the independent work are resources having the purpose of methodologically orienting the student in its independent activity, serving at the same time as a support for the dynamic of the teaching process while guiding the student in its learning, favoring autonomy, the relation between knowledge, skills and values and also community participation as scenery for performing the independent work (AU).

Management and outcomes of peripancreatic fluid collections and pseudocysts following non-operative management of pancreatic injuries in children.

BACKGROUND: Peripancreatic fluid collection and pseudocyst development is a common sequela following non-operative management (NOM) of pancreatic injuries in children. Our purpose was to review management strategies and assess outcomes. METHODS: A multicenter, retrospective review was conducted of children treated with NOM following blunt pancreatic injury at 22 pediatric trauma centers between the years 2010 and 2015. Organized fluid collections were called "acute peripancreatic fluid collection" (APFC) if identified < 4 weeks and "pseudocyst" if > 4 weeks following injury. Data analysis included descriptive statistics Wilcoxon rank-sum, Kruskal-Wallis and t tests. RESULTS: One hundred patients with blunt pancreatic injury were identified. Median age was 8.5 years (range 1-16). Forty-two percent of patients (42/100) developed organized fluid collections: APFC 64% (27/42) and pseudocysts 36% (15/42). Median time to identification was 12 days (range 7-42). Most collections (64%, 27/42) were observed and 36% (15/42) underwent drainage: 67% (10/15) percutaneous drain, 7% (1/15) needle aspiration, and 27% (4/15) endoscopic transpapillary stent. A definitive procedure (cystogastrostomy/pancreatectomy) was required in 26% (11/42). Patients with larger collections (≥ 7.1 cm) had longer time to resolution. Comparison of outcomes in patients with observation vs drainage revealed no significant differences in TPN use (79% vs 75%, p = 1.00), hospital length of stay (15 vs 25 median days, p = 0.11), time to tolerate regular diet (12 vs 11 median days, p = 0.47), or need for definitive procedure (failure rate 30% vs 20%, p = 0.75). CONCLUSIONS: Following NOM of blunt pancreatic injuries in children, organized fluid collections commonly develop. If discovered early, most can be observed successfully, and drainage does not appear to improve clinical outcomes. Larger size predicts prolonged recovery. LEVEL OF EVIDENCE: III STUDY TYPE: Case series.

Safe phlebotomy reduction in stable pediatric liver and spleen injuries.

PURPOSE: Pediatric blunt solid organ injury management based on hemodynamic monitoring rather than grade may safely reduce resource expenditure and improve outcomes. Previously we have reported a retrospectively validated management algorithm for pediatric liver and spleen injuries which monitors hemodynamics without use of routine phlebotomy. We hypothesize that stable blunt pediatric isolated splenic/liver injuries can be managed safely using a protocol reliant on vital signs and not repeat hemoglobin levels. METHODS: A prospective multi-institutional study was performed at three pediatric trauma centers. All pediatric patients from 07/2016-12/2017 diagnosed with liver or splenic injuries were identified. If appropriate for the protocol, only a baseline hemoglobin was obtained unless hemodynamic instability as defined in an age-appropriate fashion was determined by treating physician discretion. Descriptive statistics were conducted. RESULTS: One hundred four patients were identified of which 38 were excluded from the protocol. There was a significant difference in abnormal shock index, pediatric age-adjusted (SIPA) values, hematocrit, and percentage of patients with hemoglobin less than 10 between the excluded and included patients. Of the 66 patients managed on the protocol, four patients had to be removed, two each on day one and day two. Of those four patients, only one required intervention. There were no mortalities. CONCLUSION: A phlebotomy limiting protocol may be a safe option for stable pediatric splenic and liver injuries cared for in a pediatric trauma center with the resources for rapid intervention should the need arise. The differences in groups highlight the importance of utilizing this protocol in the correct patient population. Reduced phlebotomy offers the potential for reduced resource expenditure without any evidence of increased morbidity or mortality. LEVEL OF EVIDENCE: Level IV.

Decreased Pediatric Trauma Length of Stay and Improved Disposition With Implementation of Lewin's Change Model.

Although often cared for nonoperatively, trauma is a surgical disease managed by surgical services in a multidisciplinary manner. The American College of Surgeons Committee on Trauma (ACS COT) emphasizes this as part of the ACS COT verification process and expects nonsurgical service admission rate of less than 10%. In this project, we developed a collaborative care model captained by surgical services with medical service consultation to achieve this goal for optimal care of injured patients. The project was conducted at a freestanding pediatric trauma center undergoing verification as a Level 1 ACS COT pediatric trauma center. The trauma registry was utilized to obtain nonsurgical service admission rate from January 2011 to June 2015. Lewin's 3-Step Model was utilized to guide change. Adherence to the new ACS standards was continually tracked and fallouts were addressed on an individual basis. Overall compliance was reported routinely through trauma and hospital quality programs. Individual successes and accomplishments were recognized and reinforced. At the inception of the project, nonsurgical admission rate was 30%. Implementation of Lewin's 3-Step Model nonsurgical admission rate decreased to 3%, representing a reduction of 27%. In addition, a 21% reduction in hospital length of stay, 3.78-3 days, was demonstrated with no change in 30-day readmission rate. Lewin's change model facilitated culture change to achieve ACS COT standards and reduced nonsurgical admissions to less than 10%. Reduction in hospital length of stay supports an improvement in the efficiency of care when directed by the pediatric trauma surgery team.

Personalidades destacadas de las Ciencias Médicas matanceras / Outstanding personalities of the Matanzas an Medical Sciences

RESUMEN Introducción: el desarrollo histórico de las Ciencias Médicas en la provincia de Matanzas ha estado indisolublemente unido a los profesionales de la salud que han tenido el honor de participar en la formación de las nuevas generaciones. Convirtiéndose así en protagonistas de la educación médica superior. Han transcurrido 50 años desde sus inicios en la provincia. Aunque en diversos artículos sobre el tema, se destacan nombres de algunos de sus profesores, no aparece una relación de manera organizada con el aporte de cada docente a la Educación Médica Superior en la provincia. Los autores consideran que la historia debe quedar escrita para que pueda ser consultada y conocida, y, sí en su escritura se cuenta con la presencia de sus protagonistas, adquiere entonces un carácter relevante. Objetivo: escribir este artículo ha sido el propósito del grupo de Ciencias Médicas de la Asociación de Pedagogos, que incluye además de sus nombres, una síntesis de sus principales aportes. Material y métodos: se utilizaron métodos del nivel teórico y del empírico como la revisión de documentos y las entrevistas. Resultados: en este trabajo se realizó un corte hasta noviembre del año 2018, por conmemorarse en el próximo enero el 50 aniversario de la Educación Médica Superior, en Matanzas. Se presentaron los aportes de 81 personalidades con sus síntesis biográficas, todos ellos considerados profesores de alto prestigio en Matanzas. Conclusiones: se presentó las síntesis biográficas de 81 personalidades de las ciencias médicas, de alto prestigio en Matanzas para contribuir al conocimiento de la historia de la docencia médica en la provincia.

ABSTRACT Introduction: the historical development of the Medical Sciences in the province of Matanzas has been indivisibly linked to the health staff that has had the honor of participating in training the new generations of health professionals, therefore becoming protagonists of the High Medical Education. Fifty years have passed since its beginning in the province. Although the names of some of them are highlighted in several articles on the theme, there is not an organized record with the contribution of each member of the teaching staff to High Medical Education in the province. The authors considered that the history should be written for it to be consulted and known; and if history is written by the protagonists themselves, it gets a more relevant character. Objective: to write this article has been the purpose of the Medical Sciences group of the Pedagogues Association. Besides the referred professionals´ name, it includes a synthesis of their main contributions. Material and methods: there were used methods of the theoretical and the empirical level like documental review and interviews. Results: November 2018 was the last date taken into account because next January will be commemorated the 50th anniversary of high medical education in Matanzas. The contributions of 81 personalities and their biographical syntheses are presented; all of the cited personalities are considered highly prestigious professors in Matanzas. Conclusions: the biographical syntheses of 81 personalities of the medical sciences with high prestige in the province of Matanzas were presented, to contribute to the knowledge of medical teaching in the province.

C23, an oligopeptide derived from cold-inducible RNA-binding protein, suppresses inflammation and reduces lung injury in neonatal sepsis.

INTRODUCTION: Neonatal sepsis remains a leading cause of infant mortality. Cold-inducible RNA binding protein (CIRP) is an inflammatory mediator that induces TNF-α production in macrophages. C23 is a CIRP-derived peptide that blocks CIRP from binding its receptor. We therefore hypothesized that treatment with C23 reduces systemic inflammation and protects the lungs in neonatal sepsis. METHODS: Sepsis was induced in C56BL/6 mouse pups (5-7 days) by intraperitoneal injection of adult cecal slurry (0.525 mg/g body weight, LD100). One hour later pups received retroorbital injection of C23 (8 mg/kg) or vehicle (normal saline). Ten hours after sepsis induction, blood and tissues were collected for analysis. RESULTS: C23 treatment resulted in a 58% and 69% reduction in serum levels of proinflammatory cytokines IL-6 and IL-1ß, respectively, and a 40% and 45% reduction of AST and LDH, as compared to vehicle-treated septic pups. In the lungs, C23 treatment reduced expression of cytokines IL-6 and IL-1ß by 78% and 74%. In addition, the mRNA level of neutrophil chemoattractants KC and MIP-2 was reduced by 84% and 74%, respectively. These results corresponded to a reduction in histologic lung injury score. Vehicle-treated pups scored 0.49 ±â€¯0.19, while C23 treatment reduced scores to 0.29 ±â€¯0.12 (p < 0.05; Max = 1). Apoptosis in the lungs, measured by TUNEL assay, was also decreased by 53% with C23 treatment (p < 0.05). CONCLUSIONS: Inhibition of CIRP with C23 treatment is protective in septic neonatal mice as demonstrated by reduced inflammatory markers systemically and in the lung. Therefore, C23 has promising therapeutic potential in treatment of neonatal sepsis. LEVEL OF EVIDENCE: Level I.