ABSTRACT
The mortality and neurological morbidity in heatstroke have been attributed to the host's inflammatory and hemostatic responses to heat stress, suggesting that immunomodulation may improve outcome. We postulated that an experimental baboon model of heatstroke will reproduce human responses and clinical outcome to allow testing of new therapeutic strategies. Eight anesthetized juvenile baboons (Papio hamadryas) were subjected to heat stress in an incubator maintained at 44-47 degrees C until rectal temperature attained 42.5 degrees C (moderate heatstroke; n = 4) or systolic arterial pressure fell to <90 mmHg (severe heatstroke; n = 4) and were allowed to recover at room temperature. Four sham-heated animals served as a control group. Rectal temperature at the end of heat stress was 42.5 +/- 0.0 and 43.3 +/- 0.1 degrees C, respectively. All heat-stressed animals had systemic inflammation and activated coagulation, indicated by increased plasma IL-6, prothrombin time, activated partial thromboplastin time, and D-dimer levels, and decreased platelet count. Biochemical markers and/or histology evidenced cellular injury/dysfunction: plasma levels of thrombomodulin, creatinine, creatine kinase, lactic dehydrogenase, and alanine aminotransferase were increased, and varying degrees of tissue damage were present in liver, brain, and gut. No baboon with severe heatstroke survived. Neurological morbidity but no mortality was observed in baboons with moderate heatstroke. Nonsurvivors displayed significantly greater coagulopathy, inflammatory activity, and tissue injury than survivors. Sham-heated animals had an uneventful course. Heat stress elicited distinct patterns of inflammatory and hemostatic responses associated with outcome. The baboon model of heatstroke appears suitable for testing whether immunomodulation of the host's responses can improve outcome.
Subject(s)
Heat Stroke/physiopathology , Heat-Shock Response/immunology , Hemostasis/immunology , Interleukin-6/blood , Multiple Organ Failure/physiopathology , Systemic Inflammatory Response Syndrome/physiopathology , Animals , Disease Models, Animal , Heat Stroke/complications , Heat Stroke/pathology , Humans , Multiple Organ Failure/etiology , Multiple Organ Failure/pathology , Papio , Severity of Illness Index , Species Specificity , Systemic Inflammatory Response Syndrome/etiology , Systemic Inflammatory Response Syndrome/pathologyABSTRACT
Epidermal growth factor receptor (EGFR), its variant, EGFRvIII, and tenascin are glioma-associated antigens that are hyperexpressed by neoplastic glial cells relative to normal brain, making them attractive antigenic targets for immunotherapy. Preliminary surveys indicate that oligodendroglial tumors also produce these proteins, although the exact patterns and degrees of reactivity are not known. In this study we examined the immunoreactivity of tenascin among 50 oligodendroglial tumors, including 25 well-differentiated oligodendrogliomas (WDOs) and 12 glioblastomas (GBMs) exhibiting high proportions of oligodendroglia-like cells. We used well-characterized immunoreagents with defined specificities against the target antigens on formalin-fixed, paraffin-embedded archival tissue. The tumors were graded according to WHO guidelines. Immunoreactivity was reported on a 1-3 scale according to staining intensity multiplied by a 1-3 distribution scale distribution within tumor as focal (1), multifocal (2), and diffuse (3) for both the parenchymal and the perivascular components. Although there is considerable overlap in antigen production among the grades of tumor, this study establishes the production of tenascin and wild-type EGFR (but not EGFR vIII) in oligodendroglial neoplasms and supports the concept that antigen production increases with tumor grade.
