Hypertonicity contributes to seawater aspiration-induced lung injury: Role of hypoxia-inducible factor 1α.

Drowning is an important public health problem, but the mechanism of acute lung injury induced by near-drowning is rarely reported. The aim of this study is to investigate the role of hypertonicity and HIF-1α in seawater aspiration-induced lung injury. Diverse solutions were used to study the effect of hypertonicity on hypoxia, inflammation, vascular leakage, edema, and HIF-1α expression in lungs of rats. The relationship between hypertonicity and hypoxia, when they induced HIF-1α, was studied and the roles of ATM, PI3K, and p38 in the course of hypertonicity inducing HIF-1α were investigated. At last, our conclusion was verified with HIF-1α inhibitor and inducer in seawater aspiration rats. The results showed that hypertonicity, but not isotonicity and hypotonicity, promoted hypoxia, inflammation, vascular leakage, edema, and HIF-1α expression in lungs. Hypertonicity not only induced HIF-1α in a time- and dose-dependent manner but also could increase HIF-1α synergistically with hypoxia in AEC. Furthermore, hypertonicity increased HIF-1α by promoting its mRNA expression through both ATM and PI3K activation and by suppressing its protein degradation through p38 activation. During hyperosmotic stress, the increased HIF-1α promoted the production of the inflammatory cytokines in NR8383 and elevated monolayer permeability through increasing VEGF in RLMVEC. In conclusion, hypertonicity induced by aspirated seawater aggravated lung injury through increasing HIF-1α which promoted inflammation and edema in lung tissues in rats.

Underwater trauma causes a long-term specific increase in the expression of cyclooxygenase-2 in the ventral CA1 of the hippocampus.

The pro-inflammatory enzyme cyclooxygenase-2 (COX-2) is regularly expressed in the hippocampal neurons, but its role in emotional trauma is not known. Here we show that a single acute stress caused by a near-drowning experience results in heightened anxiety-like behavior one month after the trauma. Biochemical analyses of dorsal and ventral hippocampal CA1, CA3 and dentate gyrus revealed decreased ubiquitination and elevated levels of COX-2 in the traumatized animals only in the ventral CA1. To reveal the identity of the ubiquitin E3 ligase that targets COX-2, we tested the effect of several representative E3 ligases on COX-2 expression in vitro. We found that while AIP4 and Nedd4 had no effect, Mdm2 lowered COX-2 expression by nearly 50%, an effect that was not observed by its dominant negative form. To test whether this also occurs in the hippocampus, we immunoprecipitated Mdm2 from dorsal and ventral CA1 of traumatized and control animals and probed for the presence of COX-2. Our results showed that the levels of Mdm2 were not affected by the trauma but there was significantly less COX-2 associated with Mdm2 in the ventral but not dorsal CA1 of the traumatized animals. Together these data propose that an increase in COX-2 expression in ventral CA1 following trauma is likely due to its attenuated degradation. Unraveling the pathways and mechanisms that control hippocampal COX-2 degradation is important to boost the development of novel therapeutic approaches designed to treat stress-related pathologies.

Selective increase in the association of the ß2 adrenergic receptor, ß Arrestin-1 and p53 with Mdm2 in the ventral hippocampus one month after underwater trauma.

Chronic infusion of mice with a ß2 adrenergic receptor (ß2AR) analog was shown to cause long-term DNA damage in a pathway which involves ß Arresin-1-mediated activation of Mdm2 and subsequent degradation of the tumor suppressor protein p53. The objective of the present study was to test whether a single acute stress, which manifests long lasting changes in behavior, affects the interaction of Mdm2 with p53, ß2AR, and ß Arrestin-1 in the dorsal and ventral hippocampal CA1. Adult rats were subject to underwater trauma, a brief forceful submersion under water and tested a month later for behavioral and biochemical changes. Elevated plus maze tests confirmed that animals that experienced the threat of drowning present heightened levels of anxiety one month after trauma. An examination of the CA1 hippocampal areas of the same rats showed that underwater trauma caused a significant increase in the association of Mdm2 with ß2AR, ß Arrestin-1, and p53 in the ventral but not dorsal CA1. Our results provide support for the idea that stress-related events may result in biochemical changes restricted to the ventral 'emotion-related' parts of the hippocampus.

Prognostic value of proton magnetic resonance spectroscopy findings in near drowning patients: reversibility of the early metabolite abnormalities relates with a good outcome.

In two children with near drowning hypoxic encephalopathy and normal-appearing structural MRI, acute proton magnetic resonance spectroscopy ((1)H MRS) showed biochemical alterations that correctly indicated prognosis and helped to guide management decisions. Elevation of the lipid-lactate and glutamine-glutamate peaks, on the early (72 hour) (1)H MRS, predicts a poor prognosis. Absence of lipid-lactate and glutamine-glutamate peaks on the early (1)H MRS and reversibility of early mild metabolite abnormalities on follow up examination relates with good outcome.

Prognostic value of proton magnetic resonance spectroscopy findings in near drowning patients: reversibility of the early metabolite abnormalities relates with a good outcome / Valor prognóstico da espectroscopia de prótons em vítimas de quase-afogamento: reversibilidade das anormalidades metabólicas precoces relacionou-se com bom prognóstico

In two children with near drowning hypoxic encephalopathy and normal-appearing structural MRI, acute proton magnetic resonance spectroscopy (¹H MRS) showed biochemical alterations that correctly indicated prognosis and helped to guide management decisions. Elevation of the lipid-lactate and glutamine-glutamate peaks, on the early (72 hour) ¹H MRS, predicts a poor prognosis. Absence of lipid-lactate and glutamine-glutamate peaks on the early ¹H MRS and reversibility of early mild metabolite abnormalities on follow up examination relates with good outcome.

Em duas criancas vítimas de quase-afogamento com encefalopatia hipóxico-isquêmica, que apresentaram ressonância magnética por imagem normal, a espectroscopia de prótons por ressonância magnética (¹H MRS) na fase aguda mostrou alterações bioquímicas que corretamente indicaram o prognóstico e ajudaram a guiar o manejo terapêutico. Elevação dos picos de lipídeo-lactato e glutamina-glutamato na ¹H MRS precoce realizada com 72 horas previu um mau prognóstico. Relacionaram-se com bom prognóstico; a ausência dos picos de lipídeo-lactato e glutamina-glutamato na ¹H MRS precoce, e a reversibilidade no exame de controle (3 meses) das discretas anormalidades metabólicas encontradas no primeiro exame.

Clinical, laboratory and X-ray findings of drowning and near-drowning in the Gulf of Aqaba.

Clinical, laboratory and X-ray findings in 34 victims of submersion are presented. Five people died and 29 survived (age range 12-60 years). Severe hypoxia was found in all patients (mean PO2 of 58 mmHg with some oxygen support). Arterial blood gas analysis showed significant metabolic acidosis in 19 patients and significant respiratory acidosis in 15 patients. Pulmonary oedema was the most common X-ray finding. Fourteen patients were put on mechanical ventilation on the basis of their clinical picture and blood gases analysis. Clinical and laboratory data are very similar to those reported in international studies.

Apoptosis of intestinal intraepithelial lymphocytes induced by exogenous and endogenous glucocorticoids.

To investigate the effect of glucocorticoids on apoptosis in intestinal intraepithelial lymphocytes (i-IEL), we examined the changes of i-IEL followed by in vivo treatment with dexamethasone. The fragmented DNA of i-IEL were significantly increased at 15 hr after dexamethasone treatment and, subsequently, the number of total i-IEL were decreased by day 4 after treatment. Although all subsets of i-IEL including CD8 alpha/alpha(+), CD8 alpha/beta(+), CD4+ and CD4+CD8+ i-IEL were decreased after dexamethasone treatment, CD8 alpha/alpha(+) i-IEL appeared to be relatively resistant to dexamethasone-induced apoptosis. Consistent with the in vivo findings, CD8 alpha/alpha(+) i-IEL exhibited less susceptibility to dexamethasone-induced cell death in vitro than other subsets. To investigate whether this process occurs under physiological conditions, we examined the kinetics of i-IEL after treatment with 15-hr water immersion stress. In mice subjected to water immersion stress, plasma glucocorticoids were remarkably elevated soon after the 15-hr stress. The increase in the fragmented DNA of i-IEL and subsequent decrease in the number of i-IEL were observed in the stressed mice in the same kinetics as seen in the dexamethasone-treated mice. Similar to dexamethasone-induced ell death, CD8 alpha/alpha(+) i-IEL appeared to be relatively resistant to stress-induced apoptosis compared with other i-IEL subsets. The expression level of Bcl-2 was significantly higher in CD8 alpha/alpha(+) i-IEL than in CD8 alpha/beta(+) i-IEL. Our results indicate that i-IEL are subjected to cell death via apoptosis by exogenous and endogenous glucocorticoids and that different sensitivity to steroid-induced apoptosis may exist among i-IEL subsets in relation to their Bcl-2 expression.

Hypoxic encephalopathy after near-drowning studied by quantitative 1H-magnetic resonance spectroscopy.

Early prediction of outcome after global hypoxia of the brain requires accurate determination of the nature and extent of neurological injury and is cardinal for patient management. Cerebral metabolites of gray and white matter were determined sequentially after near-drowning using quantitative 1H nuclear magnetic resonance spectroscopy (MRS) in 16 children. Significant metabolite abnormalities were demonstrated in all patients compared with their age-matched normal controls. Severity of brain damage was quantified from metabolite concentrations and ratios. Loss of N-acetylaspartate, a putative neuronal marker, from gray matter preceded that observed in white matter and was more severe. Total creatine decreased, while lactate and glutamine/glutamate concentrations increased. Changes progressed with time after injury. A spectroscopic prognosis index distinguished between good outcome (n = 5) and poor outcome (n = 11) with one false negative (bad outcome after borderline MRS result) and no false positive results (100% specificity). The distinction was made with 90% sensitivity early (after 48 h) and became 100% later (by days 3 and 4). This compared with 50-75% specificity and 70-100% sensitivity based upon single clinical criteria. MRS performed sequentially in occipital gray matter provides useful objective information which can significantly enhance the ability to establish prognosis after near-drowning.

Severe hypercalcemia and polyuria in a near-drowning victim.

A 73-year-old man was admitted because of near-drowning in a hot springs bath. Transient severe hypercalcemia and polyuria were seen during the first hospital day. It seemed that the hypercalcemia was due to acute intoxication from calcium contained in the water of the spring absorbed mainly through the alveoli. To our knowledge, this is the first case of acute hypercalcemia complicating a near-drowning in a hot spring. Analysis of serum and urine electrolytes during the polyuric phase revealed saline diuresis, which was probably due to interference by the hypercalcemia of the reabsorption of sodium and free water.

Why some people do not drown. Hypothermia versus the diving response.

OBJECTIVE: To examine our present state of knowledge regarding the remarkable survival of some victims from prolonged submersion for an hour or more. Debate continues on the relative importance of the two explanatory theories--diving response and hypothermia. DATA SOURCES: A wide range of physiological, pathophysiological and clinical papers relating to the diving response, hypothermia and near-drowning, with emphasis on the period 1981-1991. DATA SYNTHESIS: The normothermic human brain suffers irreversible damage if subjected to acute asphyxia for longer than 10 minutes. Significant resistance of brain tissue to hypoxia occurs only after its temperature has fallen from 37 degrees C to 30 degrees C or less. Body surface cooling depresses core temperature by only one-third of this drop in 10 minutes. Hence an additional factor, other than hypothermia, is required to explain survival from near-drowning. The idea that ingestion and aspiration of large amounts of cold water produce such a temperature drop lacks quantitative evidence. The diving response seen in marine mammals also occurs in humans but to a lesser extent; however, about 15% of volunteers tested exhibit a profound response. This response which starts immediately upon submersion prevents aspiration of water, redistributes oxygen stores to heart and brain, slows cardiac oxygen use and initiates a hypometabolic state. The possible influence of alcohol on these processes is considered. CONCLUSIONS: Survival from prolonged near-drowning appears to depend upon a specific temporal interplay between the diving response and hypothermia, resulting in a protective state of hypometabolism.