Concomitant smoke inhalation trauma in burn patients is a serious medical problem. Previous investigations in our sheep model revealed that these injuries lead to significant airway hyperemia, enhanced pulmonary fluid extravasation, and severely impaired pulmonary function. However, the pathophysiological mechanisms are still not fully understood. The lung is innervated by sensory nerves containing peptides such as substance P and calcitonin gene-related peptide. Noxious stimuli in the airways can induce a neurogenic inflammatory response, which has previously been implicated in several airway diseases. Calcitonin gene-related peptide is known to be a potent vasodilator. We hypothesized that calcitonin gene-related peptide is also a mediator of the pulmonary reaction to toxic smoke and planned experiments to evaluate its role in this model. We tested the effects of pretreatment with a specific antagonist of the major receptor for calcitonin gene-related peptide (BIBN4096BS; 32 microg/kg, followed by continuous infusion of 6.4 microg.kg(-1).h(-1)) until the animal was killed 48 h after injury in an established ovine model of burn (40% total body surface, third degree) and smoke inhalation (48 breaths, <40 degrees C) injury. In treated animals (n = 7), the injury-related increases in tracheal blood flow and lung lymph flow were significantly attenuated compared with untreated controls (n = 5). Furthermore, the treatment significantly attenuated abnormalities in respiratory gas exchange. The data suggest that calcitonin gene-related peptide contributes to early airway hyperemia, transvascular fluid flux, and respiratory malfunction following ovine burn and smoke inhalation injury. Future studies will be needed to clarify the potential therapeutic benefit for patients with this injury.
Previous study in an ovine model of smoke inhalation and burn (S + B) injury has shown distal migration of upper airway mucus. This study examines the localization of an upper airway gland specific mucus, mucin 5B (MUC5B) in lung autopsy tissues of burn-only injury and in victims of S + B injury. We hypothesize that victims with S + B injury would exhibit increased distal migration of MUC5B than that seen in victims of burn-only injury. Autopsy lung tissue from victims of burn injury alone (n = 38) and combined S + B injury (n = 22) were immunostained for MUC5B. No normal lung tissues were included in the study. Semiquantitative analysis of the extent of MUC5B in bronchioles and parenchyma was performed on masked slides. Irrespective of injury conditions, all victims showed MUC5B in bronchioles. Mucin 5B was seen in the parenchyma except in two burn victims. No statistically significant difference was seen in the mean bronchiolar and parenchyma MUC5B scores between S + B and burn-only victims (P > 0.05). No strong statistical correlation of MUC5B scores with days postinjury or to the number of ventilatory days was evident. The percentage of pneumonia, identified histologically, was also similar between study groups. This study did not confirm our results in an ovine model of S + B injury. In contrast, virtually all pediatric burn victims, regardless of concomitant inhalation injury, showed MUC5B in their bronchioles and parenchyma. Increased mucus synthesis and/or impaired mucociliary function may contribute to the pulmonary pathophysiology associated with burn injury.
Studies in our laboratory and others have indicated that acrylonitrile (VCN) induces acute and chronic neurotoxicity and brain tumors in animal models. Reduced glutathione (GSH) depletion was suggested as the initiator of oxidative stress in VCN-induced neurotoxicity. Astrocytes possess the majority of total brain GSH and express various immunological functions that are characteristic of the brain, including the secretion of cytokines. We hypothesized that astrocytes could be the primary target of VCN's adverse activities in the brain. Therefore, VCN-induced neurotoxicity was studied by exposing proliferating normal human astrocytes (NHAs) to various concentrations of VCN (25-400 muM). We assessed cell viability; levels of endogenous antioxidants, GSH, and catalase; levels of reactive oxygen species; and secretion of TNF- alpha, a cellular marker for oxidative stress and oxidative damage to nuclear DNA, after treatment with VCN. At VCN concentrations of 25 and 50 muM, the oxidative stress markers were unaffected and at least 85% of the cells were viable. Cell viability was significantly affected at 200 and 400 muM VCN (22-42% less than control, p <. 05). The results also indicated VCN-induced depletion of GSH and a concomitant increase in levels of oxidized GSH (GSSG). The levels of total GSH and GSSG in control and treated (400 muM VCN) cells were 37 and 2, respectively. There was a significant upregulation of catalase activity (21% more than control, p <. 05) at 100 muM of VCN and a downregulation at 400 muM (40% lower than control, p <. 05). A dose-dependent, significant increase in the formation of reactive oxygen species was observed at 200 to 400 muM of VCN. Also, an elevation (two- to three fold as compared to control, p <. 05) in oxidative damage to DNA was observed at these concentrations of VCN. Increase in TNF- alphasecretion (28% higher than control, p <. 05) was observed at 400 muM VCN. Therefore, redox imbalance in astrocytes may play a major role in VCN-induced neurotoxicity, which is indicated by compromised antioxidant defense mechanisms, such as depletion of GSH, increase in GSSG, inhibition of catalase, and increase in the formation of reactive oxygen species and TNF- alphasecretion, resulting in DNA oxidation.
In a recent study, we have shown a rapid inflammatory cell influx across the glandular epithelium and strong proinflammatory cytokine expression at 4 hours after inhalation injury. Studies have demonstrated a significant role of nuclear factor kappa B in proinflammatory cytokine gene transcription. This study examines the acute airway inflammatory response and immunohistochemical detection of p65, a marker of nuclear factor kappa B activation, in sheep after smoke inhalation and burn injury. Pulmonary tissue from uninjured sheep and sheep at 4, 8, 12, 24, and 48 hours after inhalation and burn injury was included in the study. Following immunostaining for p65 and myeloperoxidase, the cell types and the percentage of bronchial submucosal gland cells staining for p65 and the extent of myeloperoxidase stained neutrophils in the bronchial submucosa were determined. Results indicate absence of detection of P65 before 12 hours after injury. At 12 hours after injury, strong perinuclear staining for p65 was evident in bronchial gland epithelial cells, macrophages, and endothelial cells. Bronchial submucosal gland cells showed a significant increase in the percentage of cells stained for p65 compared with uninjured animals and earlier times after injury, P < .05. At 24 and 48 hours after injury, p65 expression was evident in the bronchiolar epithelium, Type II pneumocytes, macrophages, and endothelial cells. Quantitation of the neutrophil influx into the bronchial submucosa showed a significant increase compared with uninjured tissue at 24 and 48 hours after injury, P < .05. In conclusion, immunohistochemical detection of activated p65 preceded the overall inflammatory response measured in the lamina propria. However, detection of p65 did not correlate with a recent study showing rapid emigration of neutrophils at 4 hours postinjury. Together, these results suggest that p65 immunostaining may identify cells that are activated to produce proinflammatory cytokines after injury; however, the immunoexpression may not adequately reflect the temporal activation of gene transcription that may occur with proinflammatory cytokine production with inhalation injury.
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