Viral transduction of renin rapidly establishes persistent hypertension in diverse murine strains.

Mice provide a unique platform to dissect disease pathogenesis, with the availability of recombinant inbred strains and diverse genetically modified strains. Leveraging these reagents to elucidate the mechanisms of hypertensive tissue injury has been hindered by difficulty establishing persistent hypertension in these inbred lines. ANG II infusion provides relatively short-term activation of the renin-angiotensinogen system (RAS) with concomitant elevated arterial pressure. Longer-duration studies using renin transgenic mice are powerful models of chronic hypertension, yet are limited by the genetic background on which the transgene exists and the exposure throughout development. The present studies characterized hypertension produced by transduction with a renin-coding adeno-associated virus (ReninAAV). ReninAAV mice experienced elevated circulating renin with concurrent elevations in arterial pressure. Following a single injection of ReninAAV, arterial pressure increased on average +56 mmHg, an increase that persisted for at least 12 wk in three distinct and widely used strains of adult mice: 129/S6, C56BL/6, and DBA/2J. This was accomplished without surgical implantation of pumps or complex breeding and backcrossing. In addition, ReninAAV mice developed pathophysiological changes associated with chronic hypertension, including increased heart weight and albuminuria. Thus ReninAAV provides a unique tool to study the onset of and effects of persistent hypertension in diverse murine models. This model should facilitate our understanding of the pathogenesis of hypertensive injury.

In vivo effect of wood smoke on the expression of two mucin genes in rat airways.

A short-term, time-dependent smoke exposure of rats in a nose-only chamber to burning wood and 24-h recovery time revealed inflammation of the airways with varying degrees of injury from loss of cilia, degeneration of epithelium, and squamous metaplasia to submucosal edema. These histological changes were reflected in variable expression of the secretory Muc5AC and low expression of membrane-associated Muc4 mucin genes. 20-min smoke exposure in extended recovery experiments showed marked disorder of tracheal epithelium for up to 72 h of recovery with a return to normal by 7 days. Gene expressions were elevated at 24 and 48 h of recovery. 30-min smoke exposure showed a more severe degeneration of the epithelium and a longer recovery time. Muc5AC expression decreased after 72 h of recovery, while there was upregulation of Muc4 gene from 48 through 96 h. Because Muc4 upregulation and histological results correlate and it has reportedly been associated with epithelium renewal, Muc4 gene may be a useful marker for the regeneration of tracheal epithelium.

Thermal injury resulting from application of a granular mineral hemostatic agent.

BACKGROUND: Uncontrolled hemorrhage accounts for the majority of deaths in combat. Effective topical hemostatic agents suitable for use on the battlefield may be valuable in controlling hemorrhage until definitive surgical intervention is possible. In an effort to identify a hemostatic agent suitable for battlefield use, we evaluated several potential hemostatic agents in a swine injury model and noted thermal injury to tissues with a granular mineral hemostatic agent (QuikClot). METHODS: Anesthetized swine were maintained with a mean arterial pressure in excess of 60 mm Hg. Cutaneous, muscular, hepatic, splenic, venous, and arterial wounds were created in a standardized fashion. Topical hemostatic agents were immediately applied to the wounds and the amount of bleeding and time to hemostasis were noted. RESULTS: The results reported here are part of a larger study in which a variety of hemostatic agents were evaluated. Only the findings related to the granular mineral hemostatic agent are discussed here. Application of the agent resulted in elevated tissue surface temperatures in excess of 95 degrees C and internal tissue temperatures exceeding 50 degrees C, 3 mm deep to the bleeding surface. Necrosis of fat and muscle were noted as well as full and partial thickness cutaneous burns. CONCLUSIONS: Topical administration of a granular mineral hemostatic agent to a variety of wounds in an experimental swine model resulted in thermal tissue injury and necrosis. Suggestions for reducing the extent of injury with this product are offered.

Recombinant factor VIIa increases the pressure at which rebleeding occurs in porcine uncontrolled aortic hemorrhage model.

In trauma patients, resuscitation to endpoints below normal blood pressure (BP) levels may reduce further blood loss due to the rebleeding often caused by more aggressive resuscitation. However, patients whose BP is maintained at lower levels for extended periods are at increased risk for organ failure. The purpose of this study was to determine whether recombinant activated factor VII (rFVIIa) raises the BP level at which rebleeding occurs in a prospective, randomized, blinded study using a porcine model of uncontrolled hemorrhage and resuscitation. Thirty anesthetized 40-kg pigs were assigned to three groups (n = 10/group): control, low-dose rFVIIa (180 microg/kg), or high-dose (720 microg/kg). Vehicle or drug was infused 5 min before creating a 2.0-mm infrarenal aortotomy. Ten minutes later, resuscitation with lactated Ringer's (LR) solution at 100 mL/min was begun. Hemorrhage and LR volumes and BP were recorded continuously. We found that pretreatment with rFVIIa increased the mean arterial pressure at which rebleeding occurred during resuscitation (45 +/- 3, 69 +/- 5, and 66 +/- 6 mmHg in the control, low-dose, and high-dose groups, respectively, P = 0.003). Rebleed hemorrhage volume was reduced with rFVIIa (39 +/- 9, 22 +/- 7, and 26 +/- 5 mL/kg for control, and low and high dose, respectively; P = 0.055). This is the first study to show that rFVIIa increases the BP at which rebleeding occurs during resuscitation in an injury to a major artery, suggesting the formation of a tight, stronger fibrin plug in the presence of high concentrations of rFVIIa.

Short report: a disseminated infection of Leishmania mexicana in an eastern woodrat, Neotoma floridana, collected in Texas.

An eastern woodrat (Neotoma floridana) collected in January 2001 near Bedias, Grimes County, Texas, had extensive lesions of both ears and swollen feet. Impression smears and histologic sections demonstrated the presence of Leishmania in both ears and the one foot that was screened. Polymerase chain reaction screening using species-specific primers detected parasites in both ears and all four feet and indicated the parasites were L. mexicana. The detection of L. mexicana in N. floridana represents a new host record in a new ecologic region and may help explain a human infection acquired outside the previously-known range of the disease. Given the geographic distribution of N. floridana and the two other species of Neotoma found naturally infected, enzootic foci of Leishmania could be present over much of the southern United States.

Effects of heparin and lisofylline on pulmonary function after smoke inhalation injury in an ovine model.

OBJECTIVE: This study evaluates the effects of heparin alone and in combination with lisofylline, 1-(5-R-hydroxyhexyl)3,7-dimethylxanthine, on severe smoke injury. DESIGN: Prospective animal study with concurrent controls. SETTING: An animal laboratory. SUBJECTS: Eighteen 1-yr-old female sheep, weighing 24-32 kg. INTERVENTIONS: After smoke exposure and tracheostomy, animals were divided into three groups. Group S (n = 6) received nebulized saline through an endotracheal tube every 4 hrs for 48 hrs. Group H (n = 6) received 10,000 units of nebulized heparin every 4 hrs. Group LH (n = 6) was treated with nebulized heparin and intravenous infusion of lisofylline (10 mg x kg(-1) x hr(-1)) for 48 hrs after a bolus injection (20 mg/kg). Animals initially breathed room air spontaneously. If PaO2 was <50 torr and PaCO2 >60 torr, animals were mechanically ventilated. Sheep were killed 48 hrs postinjury. MEASUREMENTS AND MAIN RESULTS: Blood gases were measured serially. At 48 hrs, ventilation perfusion distribution mismatching was analyzed by using the multiple inert gas elimination technique. Lung malondialdehyde was determined. The postinjury increase in alveolar-arterial oxygen tension gradient (LH, 36.7 +/- 3.5 vs. S, 89.0 +/- 24.6 torr at 48 hrs) was significantly attenuated in those animals receiving LH. The percentage of pulmonary shunt, Qs/Qt (LH, 20.8 +/- 4.9 vs. S, 36.6 +/- 4.6%), and the percentage of animals that required ventilation (LH, 0 vs. S, 67%) were significantly reduced in LH. Multiple inert gas elimination technique study showed that the true shunt fraction was decreased in LH. Lung malondialdehyde was significantly less in LH (LH, 0.33 +/- 0.06 vs. S, 0.56 +/- 0.09 nmol/mg protein). There was no significant difference in any of these variables between H and S. CONCLUSION: Treatment with heparin alone did not attenuate pulmonary dysfunction after severe smoke injury. Combined treatment with nebulized heparin and systemic lisofylline had beneficial effects on pulmonary function in association with a decrease in blood flow to poorly ventilated areas and less lipid peroxidation.