Prolonged exposure to hyperthermic stress augments neutrophil recruitment to lung during the post-exposure recovery period.

The effects of heat, especially long-term heat exposure, are complex and incompletely understood and few studies have analysed the immunological consequences of such exposures. In the present study we analysed how long-term hyperthermia modified the pulmonary immune responses, especially recruitment of neutrophils to sites of inflammation, infection and injury. Using our mouse model of long-term whole body hyperthermia (continuous 5-day passive febrile range hyperthermia (5d-FRH)) we found that bacterial lipopolysaccharide (LPS) challenge greatly increased neutrophil accumulation in bronchoalveolar lavage and lung parenchyma in 5d-FRH exposed mice in comparison to LPS-treated controls. Moreover, the effect was sustained, and persisted during the post-exposure recovery period, and LPS challenge on days 5-7 post-recovery also exhibited similarly augmented neutrophil response. Lung lavage from 5d-FRH mice, either immediately or up to 7 days post-exposure, showed significantly increased levels of ELR + CXC chemokines, KC or LIX in response to LPS challenge, indicating that enhanced chemokines could contribute to the increased recruitment of neutrophils to the lung. However, an in vivo neutrophil migration assay following 5d-FRH and during the post-exposure recovery period also showed persistently enhanced neutrophil influx in response to a fixed chemotactic gradient generated by recombinant human IL-8, suggesting that additional mechanisms besides increased ELR + CXC chemokines contributed to the augmented neutrophil response caused by 5d-FRH exposure. These previously unappreciated profound and lasting effects of long-term hyperthermia may have important consequences and may help explain the increased risk of respiratory illnesses in active duty personnel and returning veterans.

Febrile-range hyperthermia augments pulmonary neutrophil recruitment and amplifies pulmonary oxygen toxicity.

Febrile-range hyperthermia (FRH) improves survival in experimental infections by accelerating pathogen clearance, but may also increase collateral tissue injury. We hypothesized that FRH would worsen the outcome of inflammation stimulated by a non-replicating agonist and tested this hypothesis in a murine model of pulmonary oxygen toxicity. Using a conscious, temperature-controlled mouse model, we showed that maintaining a core temperature at FRH (39 degrees C to 40 degrees C) rather than at euthermic levels (36.5 degrees C to 37 degrees C) during hyperoxia exposure accelerated lethal pulmonary vascular endothelial injury, reduced the inspired oxygen threshold for lethality, induced expression of granulocyte-colony stimulating factor, and expanded the circulating neutrophil pool. In these same mice, FRH augmented pulmonary expression of the ELR(+) CXC chemokines, KC and LPS-induced CXC chemokine, enhanced recruitment of neutrophils, and changed the histological pattern of lung injury to a neutrophilic interstitial pneumonitis. Immunoblockade of CXC receptor-2 abrogated neutrophil recruitment, reduced pulmonary vascular injury, and delayed death. These combined data demonstrate that FRH may enlist distinct mediators and effector cells to profoundly shift the host response to a defined injurious stimulus, in part by augmenting delivery of neutrophils to sites of inflammation, such as may occur in infections. In certain conditions, such as in the hyperoxic lung, this process may be deleterious.