Modulation of Post-Traumatic Immune Response Using the IL-1 Receptor Antagonist Anakinra for Improved Visual Outcomes.

The purpose of this study was to characterize acute changes in inflammatory pathways in the mouse eye after blast-mediated traumatic brain injury (bTBI) and to determine whether modulation of these pathways could protect the structure and function of retinal ganglion cells (RGC). The bTBI was induced in C57BL/6J male mice by exposure to three 20 psi blast waves directed toward the head with the body shielded, with an inter-blast interval of one hour. Acute cytokine expression in retinal tissue was measured through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) four hours post-blast. Increased retinal expression of interleukin (lL)-1ß, IL-1α, IL-6, and tumor necrosis factor (TNF)α was observed in bTBI mice exposed to blast when compared with shams, which was associated with activation of microglia and macroglia reactivity, assessed via immunohistochemistry with ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein, respectively, one week post-blast. Blockade of the IL-1 pathway was accomplished using anakinra, an IL-1RI antagonist, administered intra-peritoneally for one week before injury and continuing for three weeks post-injury. Retinal function and RGC layer thickness were evaluated four weeks post-injury using pattern electroretinogram (PERG) and optical coherence tomography (OCT), respectively. After bTBI, anakinra treatment resulted in a preservation of RGC function and RGC structure when compared with saline treated bTBI mice. Optic nerve integrity analysis demonstrated a trend of decreased damage suggesting that IL-1 blockade also prevents axonal damage after blast. Blast exposure results in increased retinal inflammation including upregulation of pro-inflammatory cytokines and activation of resident microglia and macroglia. This may explain partially the RGC loss we observed in this model, as blockade of the acute inflammatory response after injury with the IL-1R1 antagonist anakinra resulted in preservation of RGC function and RGC layer thickness.

Inflammation in Fibrodysplasia Ossificans Progressiva and Other Forms of Heterotopic Ossification.

PURPOSE OF REVIEW: Heterotopic ossification (HO) is associated with inflammation. The goal of this review is to examine recent findings on the roles of inflammation and the immune system in HO. We examine how inflammation changes in fibrodysplasia ossificans progressiva, in traumatic HO, and in other clinical conditions of HO. We also discuss how inflammation may be a target for treating HO. RECENT FINDINGS: Both genetic and acquired forms of HO show similarities in their inflammatory cell types and signaling pathways. These include macrophages, mast cells, and adaptive immune cells, along with hypoxia signaling pathways, mesenchymal stem cell differentiation signaling pathways, vascular signaling pathways, and inflammatory cytokines. Because there are common inflammatory mediators across various types of HO, these mediators may serve as common targets for blocking HO. Future research may focus on identifying new inflammatory targets and testing combinatorial therapies based on these results.

CD28 Deficiency Ameliorates Blast Exposure-Induced Lung Inflammation, Oxidative Stress, Apoptosis, and T Cell Accumulation in the Lungs via the PI3K/Akt/FoxO1 Signaling Pathway.

Although CD28 is associated with the expression of inflammatory mediators, apoptosis-related protein, immunosuppression, and tumorigenesis, the effects of CD28 deficiency on blast exposure-induced lung injury have not been investigated. In this study, we have explored the effects of CD28 on blast exposure-induced lung injury and studied its potential molecular mechanisms. A mouse model of blast exposure-induced acute lung injury was established. Sixty C57BL/6 wild-type (WT) and CD28 knockout (CD28-/-) mice were randomly divided into control or model groups. Lung tissue samples were collected 24 h and 48 h after blast injury. Histopathological changes and the expressions of inflammatory-related proteins were detected by hematoxylin-eosin, immunohistochemistry, and immunofluorescence staining. Apoptosis and oxidative stress were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and reactive oxygen species (ROS). Inflammation, apoptosis, oxidative stress, and related pathway protein expression were studied by western blotting. In addition, the levels of CD3 and CD28 proteins were measured by flow cytometry. In the current study, we found that CD28 deficiency significantly inhibited blast exposure-induced increases in the lung weight/body weight ratio and wet weight/dry weight ratio; decreased the infiltration of CD44+ leukocytes, CD163+ macrophages, and CD3+ T cells into the lungs; reduced the expressions of proinflammatory cytokines including IL-1ß, TNF-α, and IL-6; and markedly increased IL-10 expression. CD28 deficiency also significantly attenuated blast exposure-induced ROS, MDA5, and IREα expressions; increased SOD-1 expression; lowered the number of apoptotic cells and Bax, Caspase-3, and active Caspase-8 expressions; and increased Bcl-2 expression. Additionally, CD28 deficiency significantly ameliorated blast exposure-induced increases of p-PI3K and p-Akt and ameliorated the decrease in the p-FoxO1 expression. Our results suggest that CD28 deficiency has a protective effect on blast exposure-induced lung injury, which might be associated with the PI3K/Akt/FoxO1 signaling pathway.

Blocking Tumor Necrosis Factor-Alpha Expression Prevents Blast-Induced Excitatory/Inhibitory Synaptic Imbalance and Parvalbumin-Positive Interneuron Loss in the Hippocampus.

Traumatic brain injury (TBI) is a major cause of neurological disorder and death in civilian and military populations. It comprises two components-direct injury from the traumatic impact and secondary injury from ensuing neural inflammatory responses. Blocking tumor necrosis factor-alpha (TNF-α), a central regulator of neural inflammation, has been shown to improve functional recovery after TBI. However, the mechanisms underlying those therapeutic effects are still poorly understood. Here, we examined effects of 3,6'-dithiothalidomide (dTT), a potentially therapeutic TNF-α inhibitor, in mice with blast-induced TBI. We found that blast exposure resulted in elevated expression of TNF-α, activation of microglial cells, enhanced excitatory synaptic transmission, reduced inhibitory synaptic transmission, and a loss of parvalbumin-positive (PV+) inhibitory interneurons. Administration of dTT for 5 days after the blast exposure completely suppressed blast-induced increases in TNF-α transcription, largely reversed blasted-induced synaptic changes, and prevented PV+ neuron loss. However, blocking TNF-α expression by dTT failed to mitigate blast-induced microglial activation in the hippocampus, as evidenced by their non-ramified morphology. These results indicate that TNF-α plays a major role in modulating neuronal functions in blast-induced TBI and that it is a potential target for treatment of TBI-related brain disorders.

CD43Lo classical monocytes participate in the cellular immune response to isolated primary blast lung injury.

BACKGROUND: Understanding of the cellular immune response to primary blast lung injury (PBLI) is limited, with only the neutrophil response well documented. Moreover, its impact on the immune response in distal organs remains poorly understood. In this study, a rodent model of isolated primary blast injury was used to investigate the acute cellular immune response to isolated PBLI in the circulation and lung, including the monocyte response, and investigate distal subacute immune effects in the spleen and liver 6 hours after injury. METHODS: Rats were subjected to a shock wave (~135 kPa overpressure, 2 ms duration) inducing PBLI or sham procedure. Rat physiology was monitored, and at 1, 3, and 6 hours thereafter, blood, lung, and bronchoalveolar lavage fluid (BALF) were collected and analyzed by flow cytometry, enzyme-linked immunosorbent assay, and histologic examination. In addition, at 6 hours, spleen and liver were collected and analyzed by flow cytometry. RESULTS: Lung histology confirmed pulmonary barotrauma and inflammation. This was associated with rises in CXCL-1, interleukin 6 (IL-6), tumor necrosis factor α and albumin protein in the BALF. Significant acute increases in blood and lung neutrophils and CD43Lo/His48Hi (classical) monocytes/macrophages were detected. No significant changes were seen in blood or lung "nonclassical" monocyte and in natural killler, B, or T cells. In the BALF, significant increases were seen in neutrophils, CD43Lo monocyte-macrophages and monocyte chemoattractant protein-1. Significant increases in CD43Lo and Hi monocyte-macrophages were detected in the spleen at 6 hours. CONCLUSION: This study reveals a robust and selective response of CD43Lo/His48Hi (classical) monocytes, in addition to neutrophils, in blood and lung tissue following PBLI. An increase in monocyte-macrophages was also observed in the spleen at 6 hours. This profile of immune cells in the blood and BALF could present a new research tool for translational studies seeking to monitor, assess, or attenuate the immune response in blast-injured patients.

Brain injury: neuro-inflammation, cognitive deficit, and magnetic resonance imaging in a model of blast induced traumatic brain injury.

Blast wave-induced traumatic injury from terrorist explosive devices can occur at any time in either military or civilian environments. To date, little work has focused on the central nervous system response to a non-penetrating blast injury. We have evaluated the effect of a single 80-psi blast-overpressure wave in a rat model. Histological and immunochemical studies showed an early inflammatory response, tissue damage and the initiation of apoptosis. With regard to inflammation, polymorphonuclear leukocytes and lymphocytes infiltrated brain parenchyma within 1 h post-blast. Glial-fibrillary protein, cyclo-oxygenase-2ir, interleukin-1ß and tumor necrosis factor were present by 1 h and remained detectable at three weeks post-injury. High mobility group box-1 protein was detectable at three weeks. With regard to tissue damage, S100ß and 4-hydroxynonenal were present at 1 h and remained detectable at three weeks. Amyloid precursor protein was detectable at three weeks. As for apoptosis, Cleaved Caspase-3 was detectable at three weeks. Morris water maze assessment of cognitive function showed that blast injured animals required significantly more time to reach the platform on day 1 of training and traveled a greater distance to get to the platform on days 1 and 2. Blast-injured animals showed a significant increase in swimming speed (p<0.001), increased total distance traveled (p<0.001) and increased number of entries into the previous quadrant that had contained the escape platform (p<0.05). Magnetic resonance imaging showed hyperintense regions in the somatosensory area within 1 h. T2 relaxation times and apparent diffusion coefficients show increasing trends in both somatosensory and cortical regions. These data indicate an early and lasting response of brain tissue to non-penetrating blast over-pressure injury. This early inflammatory response is indicative of a mild traumatic brain injury. There is evidence of early hippocampal dysfunction.

Mechanical ventilation increases the inflammatory response induced by lung contusion.

BACKGROUND: Posttraumatic lung contusion is common after blunt chest trauma, and patients often need ventilatory support. Lung contusion induces an inflammatory response signified by primed polymorph neutrophil granulocytes (PMNs) in blood and tissue. Mechanical ventilation (MV) can also cause an inflammatory response. The aim of this study was to develop an animal model to investigate the effect of high-volume ventilation on the inflammatory response in blunt chest trauma. MATERIALS AND METHODS: We assigned 23 male Sprague-Dawley rats to either MV or bilateral lung contusion followed by MV. We used three extra rats as controls. Lung contusion was induced by a blast generator, a device releasing a single pressure blast wave centered on the chest. We determined tissue and systemic inflammation by absolute PMN numbers in blood and bronchoalveolar lavage fluid (BALF), myeloperoxidase, interleukin (IL)-6, IL 1ß, growth-related oncogene-KC, and IL-10 in both plasma and BALF. RESULTS: Survival after blunt chest trauma was correlated to the distance to the blast generator. Compared with controls, both MV and blast plus MV rats showed increased systemic and pulmonary inflammation, expressed by higher PMNs, myeloperoxidase levels, and cytokine levels in both blood and BALF. Blast plus MV rats showed a higher systemic and pulmonary inflammatory response than MV rats. CONCLUSIONS: The blast generator generated reproducible blunt chest trauma in rats. Mechanical ventilation after lung contusion induced a larger overall inflammatory response than MV alone, which indicates that local damage contributes not only to local inflammation, but also to systemic inflammation. This emphasizes the importance of lung protective ventilation strategies after pulmonary contusion.

Inflammatory cytokine and chemokine expression is associated with heterotopic ossification in high-energy penetrating war injuries.

OBJECTIVE: Heterotopic ossification (HO) develops frequently after modern high-energy penetrating war injuries. The purpose of this prospective study was to identify and characterize the unique cytokine and chemokine profile associated with the development of HO as it pertained to the systemic inflammatory response after penetrating combat-related trauma. METHODS: Patients with high-energy penetrating extremity wounds were prospectively enrolled. Surgical debridement along with the use of a pulse lavage and vacuum-assisted-closure device was performed every 48-72 hours until definitive wound closure. Wound bed tissue biopsy, wound effluent, and serum were collected before each debridement. Effluent and serum were analyzed for 22 relevant cytokines and chemokines. Tissue was analyzed quantitatively for bacterial colonization. Correlations between specific wound and patient characteristics were also analyzed. The primary clinical outcome measure was the formation of HO as confirmed by radiographs at a minimum of 2 months of follow-up. RESULTS: Thirty-six penetrating extremity war wounds in 24 patients were investigated. The observed rate of HO in the study population was 38%. Of the 36 wounds, 13 (36%) demonstrated HO at a minimum follow-up of 2 months. An elevated injury severity score was associated with the development of HO (P = 0.006). Wound characteristics that correlated with the development of HO included impaired healing (P = 0.005) and bacterial colonization (P < 0.001). Both serum (interleukin-6, interleukin-10, and MCP-1) and wound effluent (IP-10 and MIP-1α) cytokine and chemokine bioprofiles were individually associated and suggestive of the development of HO (P < 0.05). CONCLUSIONS: A severe systemic and wound-specific inflammatory state as evident by elevated levels of inflammatory cytokines, elevated injury severity score, and bacterial wound colonization is associated with the development of HO. These findings suggest that the development of HO in traumatic combat-related wounds is associated with a hyper-inflammatory systemic response to injury. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Blast-induced moderate neurotrauma (BINT) elicits early complement activation and tumor necrosis factor α (TNFα) release in a rat brain.

Blast-induced neurotrauma (BINT) is a major medical concern yet its etiology is largely undefined. Complement activation may play a role in the development of secondary injury following traumatic brain injury; however, its role in BINT is still undefined. The present study was designed to characterize the complement system and adaptive immune-inflammatory responses in a rat model of moderate BINT. Anesthetized rats were exposed to a moderate blast (120 kPa) using an air-driven shock tube. Brain tissue injury, systemic and local complement, cerebral edema, inflammatory cell infiltration, and pro-inflammatory cytokine production were measured at 0.5, 3, 48, 72, 120, and 168 h. Injury to brain tissue was evaluated by histological evaluation. Systemic complement was measured via ELSIA. The remaining measurements were determined by immunohistoflourescent staining. Moderate blast triggers moderate brain injuries, elevated levels of local brain C3/C5b-9 and systemic C5b-9, increased leukocyte infiltration, unregulated tumor necrosis factor alpha (TNFα), and aquaporin-4 in rat brain cortex at 3- and 48-hour post blast. Early immune-inflammatory response to BINT involves complement and TNFα, which correlates with hippocampus and cerebral cortex damage. Complement and TNFα activation may be a novel therapeutic target for reducing the damaging effects of BINT inflammation.

Effects of bilateral adrenalectomy on the innate immune responses following trauma in rats.

BACKGROUND: The regulation of neuroendocrine hormones on the innate immune responses in trauma has not been fully understood. Previous studies have shown that the neuroendocrine hormones are important factors in their effects on immune parameters, depending on their concentration and timing instead of the simple suppressive effects. MATERIALS AND METHODS: A total of 144 Sprague­Dawley rats were divided randomly into sham, pulmonary blast injury (BI) and adrenalectomy plus pulmonary BI groups. Bilateral adrenalectomy was performed on rats, which were then subjected to blast injury. Following this, peripheral leucocyte responsiveness to lipopolysaccharide (LPS) stimulation, phagocytosis activities of macrophages and bacteria translocation (BT) were examined. Tumour necrosis factor-a (TNF-a) levels and the expression levels of scavenger receptor (SR) A, CD14, Toll-like receptor (TLR) 4 and MD2 were assayed with enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction, respectively. RESULTS: In adrenalectomised rats after pulmonary BI, the number of peripheral leucocytes was increased and the phagocytosis of peritoneal and splenic macrophages was decreased as compared to the BI group. Simultaneously, the gut-derived BT and TNF-a secretion in lung tissues were elevated, whilst the LPS-stimulated TNF-a synthesis by peripheral leucocyte responsiveness was reduced. Furthermore, the mRNA levels of SR-A, CD14, TLR4 and MD2 in lung tissues of adrenalectomised rats decreased. Adrenalectomised rats showed enhancement of inflammatory responses and severe tissue injuries in trauma. CONCLUSIONS: Release of adrenal hormones might enhance, rather than inhibit, the innate immune functions, particularly in the early stages of trauma.

Immune cytokine response in combat casualties: blast or explosive trauma with or without secondary sepsis.

The aim of this study was to assess the prognostic value of tumor necrosis factor (TNF) alpha, interleukin (IL)-8, IL-4, and IL-10 in combat casualties. Fifty-six casualties with severe trauma (blast and explosive) who developed sepsis and 20 casualties with the same severity of trauma without sepsis were enrolled in this study. Fifty-five casualties developed multiple organ dysfunction syndrome; 36 died. Blood was drawn on the first day of trauma. Concentrations of IL-8, TNF-alpha, IL-4, and IL-10 were determined in plasma using enzyme-linked immunosorbent assays. Mean values of IL-8 were 230-fold, IL-10 were 42-fold, and TNF-alpha were 17-fold higher in trauma and sepsis group (p < 0.01). Mean values of IL-8 were 60-fold, TNF-alpha were 43.5-fold, and IL-10 were 70-fold higher in the multiple organ dysfunction syndrome group (p < 0.01). Mean values of IL-8 were 2.3-fold and IL-10 were 1.4-fold higher in nonsurvivors and TNF-alpha were 2.2-fold higher in survivors (p < 0.01). IL-4 had no significance as a predictor of severity and outcome.

The quinary pattern of blast injury.

OBJECTIVE: Bombing is the primary weapon of global terrorism, and it results in a complicated, multidimensional injury pattern. It induces bodily injuries through the well-documented primary, secondary, tertiary, and quaternary mechanisms of blast. Their effects dictate special medical concern and timely implementation of diagnostic and management strategies. Our objective is to report on clinical observations of patients admitted to the Tel Aviv Medical Center following a terrorist bombing. RESULTS: The explosion injured 27 patients, and three died. Four survivors who had been in close proximity to the explosion, as indicated by their eardrum perforation and additional blast injuries, were exposed to the blast wave. They exhibited a unique and immediate hyperinflammatory state, two upon admission to the intensive care unit and two during surgery. This hyperinflammatory state manifested as hyperpyrexia, sweating, low central venous pressure, and positive fluid balance. This state did not correlate with the complexity of injuries sustained by any of the 67 patients admitted to the intensive care unit after previous bombings. CONCLUSION: The patients' hyperinflammatory behavior, unrelated to their injury complexity and severity of trauma, indicates a new injury pattern in explosions, termed the "quinary blast injury pattern." Unconventional materials used in the manufacture of the explosive can partly explain the observed early hyperinflammatory state. Medical personnel caring for blast victims should be aware of this new type of bombing injury.

Pro-inflammatory alterations and status of blood plasma iron in a model of blast-induced lung trauma.

Impact of blast shock waves (SW) with the body wall produces blast lung injuries characterized by bilateral traumatic hemorrhages. Such injuries often have no external signs, are difficult to diagnose, and therefore, are frequently underestimated. Predictive assessment of acute respiratory distress syndrome outcome in SW-related accidents should be based on experimental data from appropriate animal models. Blood plasma transferrin is a major carrier of blood iron essential for proliferative "emergency" response of hematopoietic and immune systems as well as injured tissue in major trauma. Iron-transferrin complexes (Fe3+ TRF) can be quantitatively analyzed in blood and tissue samples with low-temperature EPR techniques. We hypothesized that use of EPR techniques in combination with assays for pro-inflammatory cytokines and granulocytes in the peripheral blood and BAL would reveal a pattern of systemic sequestration of (Fe3+)TRF that could be useful for development of biomarkers of the systemic inflammatory response to lung injury. With this goal we (i) analyzed time-dependent dynamics of (Fe3+)TRF in the peripheral blood of rats after impacts of SW generated in a laboratory shock-tube and (ii) assayed the fluctuation of granulocyte (PMN) counts and expression of CD11b adhesion molecules on the surface of PMNs during the first 24 h after SW induced injury. Sham-treated animals were used as control. Exposure to SW led to a significant decrease in the amount of blood (Fe3+)TRF that correlated with the extent of lung injury and developed gradually during the first 24 h. Thus, sequestration of (Fe3+)TRF occurred as early as 3 h post-exposure. At that time, the steady state concentration of (Fe3+)TRF in blood samples decreased from 19.7+/-0.6 microM in controls to 7.5+/-1.3 microM in exposed animals. The levels of (Fe3+)TRF remained decreased throughout the entire study period. PMN counts increased 5-fold and 3.5-fold over controls respectively, at 3 and 6 h postexposure. These effects were accompanied by an increase in expression of CD11b on the surface membrane of PMNs. Extensive release of cytokines IL-1, IL-6, MCP-1, and MIP-2 was observed in BAL fluid and blood plasma during 24 h postexposure. We conclude that EPR monitoring of blood (Fe3+)TRF can be a useful approach for assessment of systemic pro-inflammatory alterations due to SW-induced lung injury.

Bilateral hand transplantation: bone healing under immunosuppression with tacrolimus, mycophenolate mofetil, and prednisolone.

PURPOSE: Little is known about bone healing after composite tissue transplantation that requires pharmacologic immunosuppression. Bone integration and callus development were assessed in bilateral hand transplantation. METHODS: In this study the course of callus development and callus maturation were assessed by color Doppler sonography and radiography in a double hand transplant and compared with forearm replantation. RESULTS: After hand transplantation, ingrowth of small vessels at the bone junction was observed at week 3, calcified callus became visible at month 4, and bone union was completed at month 11. A similar time course of bone integration was observed after replantation. Plating offered sufficient stability. A recipient periostal flap is thought to have improved blood supply and favored development and induction of callus. CONCLUSIONS: Bone healing after hand transplantation under immunosuppression with tacrolimus, mycophenolate mofetil, and prednisolone is identical to that after forearm replantation.

Assessment of inflammatory response and sequestration of blood iron transferrin complexes in a rat model of lung injury resulting from exposure to low-frequency shock waves.

OBJECTIVE: Impact of air blast overpressure waves (OPW), or shock wave, with the body wall or body armor produces two types of energy waves: high-frequency low-amplitude stress waves and long-duration low-frequency share waves. These types of energy waves are characterized by different mechanisms of primary tissue injury that mostly affect lung. Systemic inflammation and resultant acute respiratory distress syndrome are known major secondary causative agents of delayed multiple organ failure and subsequent death after OPW exposure. However, association of each pattern of the blast OPW-produced energy waves with postexposure inflammatory events has not yet been delineated. The objectives of the present research were a) establishment of a rat model for assessment of the inflammatory response following lung injury produced by exposure to medium-amplitude (approximately 120 kPa) low-frequency (260+/-5 Hz) OPWs; and b) assessment of the dynamics of alteration in polymorphonuclear leukocyte counts and expression of CD11b adhesion molecules on the surface of polymorphonuclear leukocytes and status of iron-transferrin complexes in peripheral blood after OPW exposure. DESIGN: This study focused on the OPW effects at different time periods, using a sequential approach to postexposure events. Lung injury in rat was induced by OPW generated in a laboratory shock tube. Animals were exposed to OPW (at peak overpressure of 118+/-7 kPa) that produced "moderate" lung injury. SETTING: Military research institute. SUBJECTS: Twenty-seven CVF Sprague-Dawley rats were subjected to OPW exposures, and 17 sham-treated animals were used as control. INTERVENTIONS: Lung tissue and blood samples were collected at 1, 3, 6, 12, and 24 hrs following OPW exposures and compared with samples collected from nonexposed animals. MEASUREMENTS AND MAIN RESULTS: OPW-induced lung injury caused a 2.7-fold increase in the number of circulatory polymorphonuclear leukocytes as early as 1 hr postexposure, which is indicative of mobilization of the pool of marginated polymorphonuclear leukocytes into the free circulation. Polymorphonuclear leukocyte counts increased through the following 3- and 6-hr periods, when they were, respectively, 5-fold and 3.5-fold higher than in controls. These effects were accompanied by a pronounced expression of CD11b in polymorphonuclear leukocytes and tissue sequestration of blood iron-transferrin complexes during the entire 24-hr period of observations. The increase in circulatory polymorphonuclear leukocytes was accompanied by a decrease in iron-transferrin complex concentrations that apparently reflected implication of blood plasma iron in the inflammatory cell response to OPW-induced injury. CONCLUSIONS: The observed dynamics in polymorphonuclear leukocyte alterations in peripheral blood after OPW exposure were similar to those found recently in clinical observations of nonpenetrating injury and in animal models of infectious insults. Therefore, our data suggest that the main pattern of proinflammatory alterations in the rat model of lung injury induced by exposure to long-duration shock wave is similar to patterns that are characteristic of major trauma. The data further suggest that the expression of polymorphonuclear leukocyte CD11b and the response of iron-transferrin complex can be considered as potential surrogate markers in blood for systemic alterations following OPW-induced injury and, therefore, warrant further investigation in a human pilot study.

Histologic, immunohistochemical, and ultrastructural findings in human blast lung injury.

The objective of this autopsy-based study was to investigate the pathology of human blast lung injury using histology, Fat Red 7B staining, immunohistochemistry, and scanning electron microscopy on lung specimens from eight medicolegal autopsy cases of fatal close-range detonations of chemical explosives. The micromorphologic equivalents of human blast lung injury can be summarized as follows: diffuse alveolar overdistension, circumscribed interstitial hemorrhages showing a cufflike pattern around pulmonary vessels, venous air embolism, bone marrow embolism, and pulmonary fat embolism. Hemorrhages within the lung parenchyma that were present in this study in blast victims without coexisting blunt or penetrating chest trauma must be regarded as potentially life-threatening intrapulmonary bleeding sites in survivors. In addition, the potential clinical importance of the presence of massive pulmonary fat embolism, which has, to the best of our knowledge, not been described previously in human blast lung injury, must be emphasized because pulmonary fat embolism may be a leading cause of the rapid respiratory deterioration with progressive hypoxia and development of acute respiratory distress syndrome in blast victims who survive. Furthermore, this study provides evidence that air embolism presenting in blast victims is not a mere ventilation-induced artifact.

[Effect of burn injury, blast injury and combined burn-blast injury on immune reactions of thymocytes and splenocytes in rats].

Rats were inflicted with burn (15% TBSA full-thickness) by flash thermal radiation, blast injury in shock tube (over pressure 429.3 +/- 11.5 kPa) and both of them, respectively. The dynamic changes of several cellular immune reactions of thymocytes and splenocytes were observed. One hour after injuries, the immune reactions were significantly enhanced in combined injury group as well as in blast injury group, but somewhat depressed in burn group. 12 hours after injuries, the immune reactions in all three groups were obviously depressed. It was found that the degree of depression showed an order as follows: Combined injury > Blast injury > Burn. The combined effects were more serious than that of the sum of two single injuries, and the combined injury recovered more slowly than the other two. Therefore, an aggravated effect was observed in combined injury in this experiment.