Mechanical Ventilation Exacerbates Poly (I:C) Induced Acute Lung Injury: Central Role for Caspase-11 and Gut-Lung Axis

BackgroundThe mechanisms by which moderate tidal volume ventilation (MTV) exacerbates preexisting lung injury are unclear. We hypothesized that systemic endotoxemia via the gut-lung axis would lead to non-canonical and canonical inflammasome activation and pyroptosis in a two-hit model involving polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of dsRNA and MTV and that this would associate with acute lung injury (ALI).MethodsAnesthetized mice were administered Poly(I:C) intratracheally and then 6 h later, they were mechanically ventilated for 4 h with otherwise non-injurious MTV (10ml/kg). Changes in intestinal and alveolar capillary permeability were measured. Further documentation of ALI was assessed by evans blue albumin permeability, protein and IL-1 family concentration in bronchoalveolar lavage fluid (BALF) or plasma, and histopathology in cohorts of wildtype (WT), whole body genetically ablated caspase-11 (caspase-11-/-), caspase-1/caspase-11 double knockout (caspase-1/11-/-), gasdermin D (GSDMD)-/-, nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3)-/- and advanced glycosylation end product-specific receptor (RAGE) -/- mice.ResultsNon-injurious MTV exacerbated the mild lung injury associated with Poly(I:C) administration. This included the disruption of alveolar-capillary barrier and increased levels of interleukin (IL)-6, high mobility group proteins 1 (HMGB-1), IL-1β in BALF and IL-18 in plasma. Combined (Poly(I:C)-MTV) injury was associated with increase in gastrointestinal permeability and endotoxin in plasma and BALF. Poly(I:C)-MTV injury was sensitive to caspase-11 deletion with no further contribution of caspase-1 except for maturation and release of IL-18 (that itself was sensitive to deletion of NLRP3). Combined injury led to large increases in caspase-1 and caspase-11. Genetic ablation of GSDMD attenuated alveolar-capillary disruption and release of cytokines in combined injury model.ConclusionsThe previously noted exacerbation of mild Poly(I:C)-induced ALI by otherwise non-injurious MTV is associated with an increase in gut permeability resulting in systemic endotoxemia. The gut-lung axis resulted in activation of pulmonary non-canonical (cytosolic mediated caspase-11 activation) and canonical (caspase-1) inflammasome (NLRP3) mediated ALI in this two-hit model resulting in GSDMD sensitive alveolar capillary barrier disruption, pyroptosis (alveolar macrophages) and cytokine maturation and release (IL-1β; IL-18). Pharmacologic strategies aimed at disrupting communication between gut and lung, inhibition of inflammasomes or GSDMD in pyroptosis may be useful in ALI.

Incidence and missed diagnosis risk of occult posterior malleolar fractures associated with the tibial shaft fractures: a systematic review

Background Tibial shaft fractures (TSFs) combined with occult posterior malleolar fractures (PMFs) are becoming widely recognized in the field of orthopedics. The purpose of this study was to determine the clinical incidence, missed diagnosis rate, and treatment strategies of this combined injury. Methods PubMed, Cochrane, and MEDLINE Ovid databases were searched for articles of English language from 1988 to 2020, identifying 1549 papers. Results Twenty-one of the 1278 identified studies were eligible for inclusion. Each study reported on the incidence of this combined injury, and 12 studies documented the missed diagnosis rate. Seventeen studies reported surgical intervention strategies for PMFs. In the present review, PMFs frequently occurred in spiral TSFs (70%), especially distal third spiral TSFs (70.4%), based on CT scans or additional MRI. Based on the original X-ray detection, approximately 50% of PMFs were missed in patients with a combined injury. In addition, the treatment strategies for PMFs were inconsistent. Most studies (11/17) believe that specific surgical management needs to be developed based on the fragment size, displacement, and stability of the PMF. Conclusions For patients with TSFs, spiral TSFs, especially distal third spiral TSFs, are closely related to PMFs and are often not sufficiently diagnosed by X-ray alone. Advanced CT and MRI examinations can significantly reduce the missed diagnosis rate of occult PMFs. According to available literature, the treatment strategy for PMFs associated with TSFs is questionable without convincing evidence of benefit.

Extracorporeal detoxification techniques in septic complications in children at the acute stage of severe combined injury

Relevance. The given literature review analyzes current approaches to the extracorporeal detoxification (ECD) in ICU in patients with sepsis. In case of severe polytrauma in a child, anatomical and physiological features of his/her organism, marked severity and rapid progression of multiple organ failure as well problems in taking anamnesis put specialists into a challenging situation. A pathogenetically differentiated approach to the choice of extracorporeal detoxification technique in the complex treatment of sepsis – with respect to the syndrome of endogenous intoxication - will increase the effectiveness of therapeutic measures of intensive care in children at their acute stage after severe combined injuryObjective. To improve outcomes in children at the acute stage of severe combined injury by applying differentiated techniques for extracorporeal detoxification in septic complications .Material and methods. The most common techniques were analyzed: hemosorption, plasmapheresis, prolonged veno-venous hemofiltration and hemodiafiltration.Results. A large number of works have been published which confirm ECD effectiveness in adult patients with severe sepsis and septic shock. However, in the available literary sources, there are almost no information on the differentiated approach to various ECD techniques in children with severe combined injury who have traumatic endotoxicosis and multiple organ failure. Conclusion. Clinical trials and prospective researches on practical aspects of extracorporeal treatment in pediatrics are priority and compulsory because of the gained world experience of its application in patients with septic endotoxicosis. This impels towards further clinical researches in this direction.

Early Reciprocal Effects in a Murine Model of Traumatic Brain Injury and Femoral Fracture

Traumatic brain injury (TBI) represents a major cause of death and disability in early adulthood. Concomitant extracranial injury such as long bone fracture was reported to exacerbate TBI pathology. However, early reciprocal effects and mechanisms have been barely investigated. To address this issue, C57BL/6N mice were subjected to either the controlled cortical impact (CCI) model of TBI, fracture of the left femur (FF), combined injury (CCI+FF), or sham procedure. Behavioral alterations were monitored until 5 days post injury (dpi), followed by (immuno-)histology, gene and protein expression analyses using quantitative PCR, western blot, and ELISA. We found that CCI+FF mice exhibited increased neurological impairments, reduced recovery, and altered anxiety-related behavior compared to single injury groups. At 5 dpi, cerebral lesion size was not affected by combined injury but exaggerated hippocampal substance loss and increased perilesional astrogliosis were observed in CCI+FF mice compared to isolated CCI. Bone gene expression of the osteogenic markers Runx2, osteocalcin, alkaline phosphatase, and bone sialoprotein was induced by fracture injury but attenuated by concomitant TBI. Plasma concentrations of the biomarkers osteopontin and progranulin were elevated in CCI+FF mice compared to other experimental groups. Taken together, using a murine model of TBI and femoral fracture, we report early reciprocal impairments of brain tissue maintenance, behavioral recovery, and bone repair gene expression. Increased circulating levels of the biomarkers osteopontin and progranulin indicate ongoing tissue inflammation and repair. Our results may have implications for future therapeutic approaches to interfere with the pathological crosstalk between TBI and concomitant bone fracture.

Combined injury of extrahepatic biliary ducts and right hepatic artery in laparoscopic cholecystectomy

Combined injury of extrahepatic biliary ducts and right hepatic artery in laparoscopic cholecystectomy

Mechanical Ventilation Exacerbates Poly (I:C) Induced Acute Lung Injury: Central Role for Caspase-11 and Gut-Lung Axis

Background: The mechanisms by which moderate tidal volume ventilation (MTV) may exacerbate preexisting lung injury remain unclear. We hypothesized that in two hit model (polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of dsRNA and MTV), systemic endotoxemia via gut-lung axis would lead to non-canonical (i.e. caspase-11 dependent) and canonical (caspase-1 dependent) inflammasome activation and programmed necrotic cell death (pyroptosis) contributing to acute lung injury (ALI) in intact mice.Methods: Anesthetized mice were administered Poly(I:C) intratracheally and then 6 h later, they were mechanically ventilated for 4 h with otherwise non-injurious MTV (10ml/kg). Changes in intestinal and alveolar capillary permeability were measured. Further documentation of ALI was assessed by evans blue albumin permeability, protein and IL-1 family concentration in bronchoalveolar lavage fluid (BALF) or plasma, and histopathology in cohorts of wildtype, whole body genetically ablated caspase-11 (caspase-11-/-), caspase-1/caspase-11 double knockout (caspase-1/11-/-), gasdermin D (GSDMD-/-), and NLRP3-/- mice. Results: Non-injurious MTV exacerbated mild Poly(I:C) lung injury including disruption of alveolar-capillary barrier and increased levels of IL-6, HMGB1, IL-1β in BALF and IL-18 in plasma. Combined (Poly(I:C)-MTV) injury was associated with increase in gastrointestinal permeability and endotoxin in plasma and BALF. Poly(I:C)-MTV injury was sensitive to caspase-11 deletion with no further contribution of caspase-1 except for maturation and release of IL-18 (that itself was sensitive to deletion of NLRP3). Combined injury led to large increases in pro-caspase-11 and its cleaved product as well as cleaved product of caspase-1. Genetic ablation of GSDMD attenuated alveolar-capillary disruption and maturation and release of cytokines in combined injury model.Conclusions: The previously noted TLR-4 independent exacerbation of mild Poly(I:C)-induced ALI by otherwise non-injurious MTV is associated with an increase in gut permeability resulting in systemic endotoxemia. The gut-lung axis resulted in activation of pulmonary non-canonical (cytosolic mediated caspase-11 activation) and canonical (caspase-1) inflammasome (NLRP3) mediated ALI in this two hit model resulting in GSDMD sensitive alveolar capillary barrier disruption, pyroptosis (in alveolar macrophages) and cytokine maturation and release (IL-1β; IL-18). Pharmacologic strategies at disrupting communication between gut and lung, inhibition of inflammasomes or effector molecule (GSDMD) in pyroptosis may be useful in ALI.

The experience of using “ChitoPran” wound coating for treating a patient with combined injury

Background. Resolution of problems related to burn injuries remains relevant and extremely complex in the modern medicine. Biological wound coatings are actively used in the treatment of patients with burn injury. Researchers at the Scientific Research Institute at the Ochapovsky Regional Clinical Hospital No. 1 have been using the biological wound coating ChitoPran since 2017. This coating creates a dry environment in the wound for borderline depth burns and after autoplasty, which contributes to the acceleration of epithelization. For deeper burns after necrectomy, the ChitoPran accelerates the growth of granulation tissues. Clinical case. This article presents the clinical case of the successful treatment of a 17-year-old burn patient with a combined injury. The patient presented with a blunt abdominal injury on the background of a deep burn of the anterior abdominal wall. The patient underwent a median laparotomy on the first day and an early necrectomy with primary cutaneous autoplasty with the ChitoPran closing of the wounds on a day later. Discussion. The use of the ChitoPran wound coating in combination with skin autoplasty for the early surgical treatment of burns contributes to the acceleration of epithelization of wounds in comparison with stage-based surgical treatment. This coating is hence comparable in terms of cellular epithelization with the use of fibroblasts. Conclusions. Creating optimal conditions for epithelization in the wound can prevent the development of purulent complications (such as the failure of skin sutures of the anterior abdominal wall). The use of ChitoPran wound coating showed improved outcomes in the treatment of patients with burn injuries through accelerated restoration of the skin and reduced suppuration in the wound.