Fever, hyperthermia, and the lung: it's all about context and timing

Abstract

Although body temperature is tightly regulated in humans, elevated temperatures are frequently encountered during febrile illnesses and exertional and environmental hyperthermia. Such temperature increases exert profound effects on cell signaling and gene expression patterns, which have important consequences for innate immune function and cell injury, apoptosis, and recovery. The lung offers a framework for understanding how these effects can either benefit or harm the host. We present data demonstrating that exposure to febrile-range hyperthermia (∼39.5 °C) exerts multiple biologic effects that converge on enhanced neutrophil recruitment to the lung, and describe the consequences of these effects for pathogen clearance and collateral tissue injury. We also discuss the influence of temperature on apoptosis in lung epithelium. Collectively, the data presented identify body temperature as a modifiable factor that exerts profound influence on the outcome of infection and injury.

Fig. 1

Comparison of FRH effects on experimental Klebsiella pneumoniae peritonitis and pneumonia. Bacterial load experiments: Mice were inoculated with 100 CFU of K. pneumoniae via intraperitoneal injection in 1 mL PBS (Panel A) or 250 CFU K. pneumoniae via intratracheal instillation in 50 μL PBS (Panel B), and then housed at 25°C (normothermia) or 35–37°C to maintain a core temperature of ∼39.5°C (FRH). Groups of 6 normothermic and FRH-exposed mice were sequentially euthanized and the bacterial load in the animals' peritoneal fluid (Panel A) and in homogenized lung tissue (Panel B) was quantified by culturing and counting colonies. Values are given as mean ± SE;* P < 0.05 versus normothermic mice. Survival experiments: Groups of 8 to 10 mice were inoculated with K. pneumoniae via intraperitoneal injection (Panel C) or via intratracheal instillation (Panel D) and were, then housed under conditions of normothermia or FRH and their survival monitored. Duplicate experiments were performed. Febrile ranger hyperthermia improved survival in the peritonitis model (Panel C) but not the pneumonia model (Panel D) by a log rank test.

Fig. 2

Effect of exposure to FRH on LPS-induced acute lung injury. Mice received instillations of 50 μg LPS in 50 μL PBS and were then housed at 25°C (Panels A and C) or at 35–37°C to maintain a core temperature of ∼39.5°C (Panels B and D). Mice were euthanized after 24 hours and their lungs fixed in Prefer™ fixative at 20 cm H₂O pressure. Representative pictures of the inflated lungs (Panels A and B) and micrographs of lung tissue stained for neutrophils with anti-GR-1 antibody (Panels C and D) are shown. Neutrophils appear as brown-staining cells.

Fig. 3

Metabolic consequences of external cooling in febrile, critically ill patients. Six patients with SIRS and persistent fever >38.3°C despite receiving acetaminophen were subjected to physical cooling with two Cincinnati Sub-zero Blanketrol II cooling blankets set to 4°C, with one blanket above and one below the patient, and with axillary and inguinal icepacks. Vo₂ was measured with a Viasys Vmax 229 metabolic cart for 15 minutes before cooling, and the measurement was repeated every 15 minutes during a 90-minute cooling period. Values are given as mean ± SE.