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Steroid-Loaded Hemostatic Nanoparticles Combat Lung Injury after Blast Trauma.

ABSTRACT: In response to the lack of therapeutics for internal bleeding following a traumatic event, we synthesized hemostatic dexamethasone nanoparticles (hDNP) to help alleviate internal hemorrhaging. hDNP consist of a block copolymer, poly(lactic-co-glycolic acid)-poly(l-lysine)-poly(ethylene glycol) conjugated to a peptide, glycine-arginine-glycine-aspartic acid-serine (GRGDS). These particles were evaluated as treatment for primary blast lung injury in a rodent model. Animals were randomly placed into test and control groups, exposed to blast and given immediate injection. Recovery was assessed using physiological parameters and immunohistochemistry. We found that dexamethasone-loaded hemostatic nanoparticles alleviate physiological deprivation caused by blast injury and reduce lung injury damage.

SUBMITTER: Hubbard WB

PROVIDER: S-EPMC5033257 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Steroid-Loaded Hemostatic Nanoparticles Combat Lung Injury after Blast Trauma.

Hubbard William B WB Lashof-Sullivan Margaret M MM Lavik Erin B EB VandeVord Pamela J PJ

ACS macro letters 20150323 4

In response to the lack of therapeutics for internal bleeding following a traumatic event, we synthesized hemostatic dexamethasone nanoparticles (hDNP) to help alleviate internal hemorrhaging. hDNP consist of a block copolymer, poly(lactic-co-glycolic acid)-poly(l-lysine)-poly(ethylene glycol) conjugated to a peptide, glycine-arginine-glycine-aspartic acid-serine (GRGDS). These particles were evaluated as treatment for primary blast lung injury in a rodent model. Animals were randomly placed int ...[more]

PMID: 27668129

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Project description:ObjectiveTo determine whether a structured and quantitative assessment of differential olfactory performance-recognized between a blast-injured traumatic brain injury (TBI) group and a demographically comparable blast-injured control group-can serve as a reliable antecedent marker for preclinical detection of intracranial neurotrauma.MethodsWe prospectively and consecutively enrolled 231 polytrauma inpatients, acutely injured from explosions during combat operations in either Afghanistan or Iraq and requiring immediate stateside evacuation and sequential admission to our tertiary care medical center over a 2½-year period. This study correlates olfactometric scores with both contemporaneous neuroimaging findings as well as the clinical diagnosis of TBI, tabulates population-specific incidence data, and investigates return of olfactory function.ResultsOlfactometric score predicted abnormal neuroimaging significantly better than chance alone (area under the curve = 0.78, 95% confidence interval [CI] 0.70-0.87). Normosmia was present in all troops with mild TBI (i.e., concussion) and all control subjects. Troops with radiographic evidence of frontal lobe injuries were 3 times more likely to have olfactory impairment than troops with injuries to other brain regions (relative risk 3.0, 95% CI 0.98-9.14). Normalization of scores occurred in all anosmic troops available for follow-up testing.ConclusionQuantitative identification olfactometry has limited sensitivity but high specificity as a marker for detecting acute structural neuropathology from trauma. When considering whether to order advanced neuroimaging, a functional disturbance with central olfactory impairment should be regarded as an important tool to inform the decision process.Classification of evidenceThis study provides Class III evidence that central olfactory dysfunction identifies patients with TBI who have intracranial radiographic abnormalities with a sensitivity of 35% (95% CI 20.6%-51.7%) and specificity of 100% (95% CI 97.7%-100.0%).

Project description:RationaleAcute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology.ObjectivesTo investigate the pathological roles of circulating histones in trauma-induced lung injury.MethodsCirculating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause-effect relationship was studied using cells and mouse models.Measurements and main resultsIn a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality.ConclusionsThis study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival outcomes in patients.

Project description:To investigate the protective effect of chitosan oligosaccharide (COS) on acute lung injury (ALI) caused by blast injury, and explore possible molecular mechanisms.A mouse model of blast injury-induced ALI was established using a self-made explosive device. Thirty mice were randomly assigned to control, ALI and ALI + COS groups. An eight-channel physiological monitor was used to determine the mouse physiological index. Enzyme linked immunosorbent assay was used to measure serum inflammatory factors. Hematoxylin-eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, immunofluorescence staining, real time-polymerase chain reaction and western blot assay were used to detect inflammatory reactions, oxidative stress and apoptosis.Mice were sacrificed 24 hours after successful model induction. Compared with the ALI group, the heart rate, respiration and PCO2 were significantly lower, but the PO2, TCO2 and HCO3- were significantly higher in the ALI + COS group. Compared to ALI alone, COS treatment of ALI caused a significant decrease in the wet/dry lung weight ratio, indicating a reduction in lung edema, inflammatory cell infiltration, levels of tumor necrosis factor-?, interleukin (IL)-1?, IL-4, IL-6 and nuclear factor kappa B mRNA and protein expression were reduced and IL-10 mRNA and protein expression was increased (P < 0.05). COS significantly inhibited reactive oxygen species, MDA5 and IRE? mRNA and protein expressions, cell apoptosis and Bax and Caspase-3 mRNA and protein expressions, and significantly increased superoxide dismutase-1 mRNA expression, and Bcl-2 and Caspase-8 mRNA and protein expression (all P<0.05). COS significantly increased dimethylarginine dimethylaminohydrolase 1 (DDAH1) protein expression, and reduced ADMA and p38 protein expression (P< 0.05).Blast injury causes inflammation, oxidative stress and apoptosis in the lung tissues of mice. COS has protective effects on blast injury-induced ALI, possibly by promoting DDAH1 expression and inhibiting ADMA and mitogen-activated protein kinase pathways.

Project description:The etiology of trauma-hemorrhage shock-induced acute lung injury has been difficult to elucidate due, at least in part, to the inability of in vivo studies to separate the non-injurious pulmonary effects of trauma-hemorrhage from the tissue injurious ones. To circumvent this in vivo limitation, we utilized a model of trauma-hemorrhagic shock (T/HS) in which T/HS-lung injury was abrogated by dividing the mesenteric lymph duct. In this way, it was possible to separate the pulmonary injurious response from the non-injurious systemic response to T/HS by comparing the pulmonary molecular response of rats subjected to T/HS which did and did not develop lung injury as well as to non-shocked rats. Utilizing high-density oligonucleotide arrays and treatment group comparisons of whole lung tissue collected at 3 hours after the end of the shock or sham-shock period, 139 of the 8,799 assessed genes were differentially expressed. Experiment Overall Design: Four groups of rats (n=3) were studied in order to identify changes in pulmonary gene expression associated with T/HS, both in the presence and absence of lung injury. These included trauma-sham shock (T/SS) rats which had a laparotomy (trauma) but were not subjected to hemorrhagic shock. These rats had no lung injury and served as controls for rats which were subjected to T/HS (laparotomy plus 90 min of shock) and had lung injury. Differences in gene expression between these two groups would represent both the effects of hemorrhagic shock as well as lung injury. To distinguish the gene response of hemorrhagic shock from the gene response associated with lung injury, gene expression was also compared between T/HS rats (hemorrhage and lung injury) and rats subjected to T/HS plus lymph duct ligation (T/HS-LDL), since the T/HS-LDL rats experienced hemorrhagic shock but had no measurable lung injury. Lastly, to identify hemorrhagic shock- modified genes, the pulmonary gene response of T/HS-LDL (hemorrhage without lung injury) were compared to rats subjected to T/SS plus LDL (no hemorrhage or lung injury). Three hours after the end of the 90 min shock or sham-shock period (i.e. 4.5 hrs after the induction of T/HS), the rats were sacrificed and specimens harvested for genechip analysis and histology.

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Steroid-Loaded Hemostatic Nanoparticles Combat Lung Injury after Blast Trauma.

Publications

Steroid-Loaded Hemostatic Nanoparticles Combat Lung Injury after Blast Trauma.

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