Febrile-Range Hyperthermia Augments Neutrophil Accumulation and Enhances Lung Injury in Experimental Gram-Negative Bacterial Pneumonia

Abstract

We previously demonstrated that exposure to febrile-range hyperthermia (FRH) accelerates pathogen clearance and increases survival in murine experimental Klebsiella pneumoniae peritonitis. However, FRH accelerates lethal lung injury in a mouse model of pulmonary oxygen toxicity, suggesting that the lung may be particularly susceptible to injurious effects of FRH. In the present study, we tested the hypothesis that, in contrast with the salutary effect of FRH in Gram-negative peritonitis, FRH would be detrimental in multilobar Gram-negative pneumonia. Using a conscious, temperature-clamped mouse model and intratracheal inoculation with K. pneumoniae Caroli strain, we showed that FRH tended to reduce survival despite reducing the 3 day-postinoculation pulmonary pathogen burden by 400-fold. We showed that antibiotic treatment rescued the euthermic mice, but did not reduce lethality in the FRH mice. Using an intratracheal bacterial endotoxin LPS challenge model, we found that the reduced survival in FRH-treated mice was accompanied by increased pulmonary vascular endothelial injury, enhanced pulmonary accumulation of neutrophils, increased levels of IL-1β, MIP-2/CXCL213, GM-CSF, and KC/CXCL1 in the bronchoalveolar lavage fluid, and bronchiolar epithelial necrosis. These results suggest that FRH enhances innate host defense against infection, in part, by augmenting polymorphonuclear cell delivery to the site of infection. The ultimate effect of FRH is determined by the balance between accelerated pathogen clearance and collateral tissue injury, which is determined, in part, by the site of infection.

Hyperthermia in the febrile range induces HSP72 expression proportional to exposure temperature but not to HSF-1 DNA-binding activity in human lung epithelial A549 cells

“…A computerassisted analysis of CXC chemokine promoters showed that almost every member of this family of neutrophil chemotaxins contains HSEs within their promoter sequences, suggesting these genes may be a newly recognized class of HSF-1-regulated genes (Nagarsekar et al 2005). In further support of the link between febrile-range temperatures and genes-regulating neutrophil recruitment, we found that exposure to febrile-range hyperthermia (core temperature 39.5°C) increases expression of CXC chemokines, augments neutrophil recruitment, and increases tissue injury in mouse models of lung injury (Hasday et al 2003;Rice et al 2005); however, augmentation of CXC chemokine expression did not occur in HSF-1-null mice ). These data demonstrate how activation of HS pathways at febrile-range temperatures has effects beyond HSP expression that may have important consequences in the febrile host.…”

“…We and others have demonstrated that elements of the HS response are activated at febrile-range temperatures and regulate genes involved in inflammation and the innate immune response, including tumor necrosis factor α (Ostberg et al 2000;Singh et al 2002Singh et al , 2000, interleukin (IL)-1β (Cahill et al 1996;Fairchild et al 2000), IL-8, and granulocyte macrophage colony-stimulating factor (Rice et al 2005;Singh et al 2008), as well as HSPs. A computerassisted analysis of CXC chemokine promoters showed that almost every member of this family of neutrophil chemotaxins contains HSEs within their promoter sequences, suggesting these genes may be a newly recognized class of HSF-1-regulated genes (Nagarsekar et al 2005).…”

Contrasting Effects of Cyclooxygenase-1 (COX-1) and COX-2 Deficiency on the Host Response to Influenza A Viral Infection

“…Neutrophils play an important role in the clearance of virus from the infected lungs. Neutrophils also play an important role in the pathophysiology of influenza as they cause narrowing of terminal bronchi and bronchioli (29), and they are a significant source of tissue injury during the innate immune response (46). Consequently, a fine balance exists between the ability of the host immune system to clear the virus and the damage that this immune response causes to the delicate architecture of the lung.…”

Toll-like Receptor Agonists and Febrile Range Hyperthermia Synergize to Induce Heat Shock Protein 70 Expression and Extracellular Release

“…For LPS instillation, the mice were briefly anesthetized with isoflurane, and 50 g of LPS in 50 l of PBS was administered into the posterior pharynx with the tongue retracted until aspiration was witnessed. Twenty-four hours later, the mice were euthanized by isoflurane inhalation and cervical dislocation, and either lungs were resected and frozen in liquid nitrogen for homogenization in radioimmune precipitation assay buffer or lung lavage was performed with a total of 2 ml of PBS as we have previously described (33,35,36).…”