Image-guided treatment of cancer enables physicians to localize and treat tumors with great precision. Here, we present in vivo results showing that an emerging imaging modality, magnetic particle imaging (MPI), can be combined with magnetic hyperthermia into an image-guided theranostic platform. MPI is a noninvasive 3D tomographic imaging method with high sensitivity and contrast, zero ionizing radiation, and is linearly quantitative at any depth with no view limitations. The same superparamagnetic iron oxide nanoparticle (SPIONs) tracers imaged in MPI can also be excited to generate heat for magnetic hyperthermia. In this study, we demonstrate a theranostic platform, with quantitative MPI image guidance for treatment planning and use of the MPI gradients for spatial localization of magnetic hyperthermia to arbitrarily selected regions. This addresses a key challenge of conventional magnetic hyperthermia—SPIONs delivered systemically accumulate in off-target organs (e.g., liver and spleen), and difficult...

/pdf/magnetic-particle-imaging-guided-heating-in-vivo-using-yyjdyuuatl.pdf

Magnetic Particle Imaging-Guided Heating in Vivo Using Gradient Fields for Arbitrary Localization of Magnetic Hyperthermia Therapy

A single layer of enterocytes and tight junctions (intercellular multiprotein complexes) form the intestinal epithelial barrier that controls transport of molecules through transcellular and paracellular pathways. A dysfunctional or "leaky" intestinal tight junction barrier allows augmented permeation of luminal antigens, endotoxins, and bacteria into the blood stream. Various substances and conditions have been shown to affect the maintenance of the intestinal epithelial tight junction barrier. The primary focus of the present review is to analyze the effects of exertional or nonexertional (passive hyperthermia) heat stress on tight junction barrier function in in vitro and in vivo (animals and humans) models. Our secondary focus is to review changes in tight junction proteins in response to exercise or hyperthermic conditions. Finally, we discuss some pharmacological or nutritional interventions that may affect the cellular mechanisms involved in maintaining homeostasis of the intestinal epithelial tight junction barrier during heat stress or exercise.

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.00536.2015

Intestinal epithelial barrier function and tight junction proteins with heat and exercise.

There are numerous causes of a raised core temperature. A fever occurring in sepsis may be associated with a survival benefit. However, this is not the case for non-infective triggers. Where heat generation exceeds heat loss and the core temperature rises above that set by the hypothalamus, a combination of cellular, local, organ-specific, and systemic effects occurs and puts the individual at risk of both short-term and long-term dysfunction which, if severe or sustained, may lead to death. This narrative review is part of a series that will outline the pathophysiology of pyrogenic and non-pyrogenic fever, concentrating primarily on the pathophysiology of non-septic causes.

/pdf/the-pathophysiological-basis-and-consequences-of-fever-4ssjdn1afr.pdf

The pathophysiological basis and consequences of fever.

Acute heat stress (HS) and heat stroke can be detrimental to the health, well-being, and performance of mammals such as swine. Therefore, our objective was to chronologically characterize how a growing pig perceives and initially copes with a severe heat load. Crossbred gilts (n=32; 63.8±2.9 kg) were subjected to HS conditions (37°C and 40% humidity) with ad libitum intake for 0, 2, 4, or 6 h (n=8/time point). Rectal temperature (Tr), respiration rates (RR), and feed intake were determined every 2 h. Pigs were euthanized at each time point and fresh ileum and colon samples were mounted into modified Ussing chambers to assess ex vivo intestinal integrity and function. Transepithelial electrical resistance (TER) and fluorescein isothiocyanate-labeled dextran (FD4) permeability were assessed. As expected, Tr increased linearly over time (P<0.001) with the highest temperature observed at 6 h of HS. Compared to the 0-h thermal-neutral (TN) pigs, RR increased (230%; P<0.001) in the first 2 h and remained elevated over the 6 h of HS (P<0.05). Feed intake was dramatically reduced due to HS and this corresponded with significant changes in plasma glucose, ghrelin, and glucose-dependent insulinotropic peptide (P<0.050). At as early as 2 h of HS, ileum TER linearly decreased (P<0.01), while FD4 linearly increased with time (P<0.05). Colon TER and FD4 changed due to HS in quadratic responses over time (P=0.050) similar to the ileum but were less pronounced. In response to HS, ileum and colon heat shock protein (HSP) 70 mRNA and protein abundance increased linearly over time (P<0.050). Altogether, these data indicated that a short duration of HS (2-6 h) compromised feed intake and intestinal integrity in growing pigs.

https://lib.dr.iastate.edu/cgi/viewcontent.cgi?article=1119&context=fshn_ag_pubs

Short-term exposure to heat stress attenuates appetite and intestinal integrity in growing pigs.

Background Stress of different origin is known to alter so called "braingut axis" and contributes to a broad array of gastrointestinal disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal diseases. The stressful situations and various stressors including psychosocial events, heat, hypo- and hyperthermia may worsen the course of IBD via unknown mechanism. The aims of this paper were to provide an overview of experimental and clinical evidences that stress activates the brain-gut axis which results in a mucosal mast cells activation and an increase in the production of proinflammatory cytokines and other endocrine and humoral mediators. Methods Research and online content related to effects of stress on lower bowel disorders are reviewed and most important mechanisms are delineated. Results Brain conveys the neural, endocrine and circulatory messages to the gut via brain-gut axis reflecting changes in corticotrophin releasing hormone, mast cells activity, neurotransmission at the autonomic nerves system and intestinal barrier function all affecting the pathogenesis of animal colitis and human IBD. Stress triggers the hypothalamus-pituitary axis and the activation of the autonomic nervous system, an increase in cortisol levels and proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-8, interleukin-1beta and interleukin-6. Conclusion The acute or chronic stress enhances the intestinal permeability weakening of the tight junctions and increasing bacterial translocation into the intestinal wall. An increased microbial load in the colonic tissue, excessive cytokine release and a partially blunted immune reactivity in response to stress result in its negative impact on IBD.

/pdf/mechanisms-by-which-stress-affects-the-experimental-and-3gaq7932mc.pdf

Mechanisms by which Stress Affects the Experimental and Clinical Inflammatory Bowel Disease (IBD). Role of Brain-Gut Axis.

It is likely that the pathophysiology of exertional heat stroke (EHS) differs from passive heat stroke (PHS), but this has been difficult to verify experimentally. C57Bl/6 mice were instrumented wi...

Biomarkers of multiorgan injury in a preclinical model of exertional heat stroke

Key points

Heat stroke afflicts thousands of humans each year, worldwide.
The immune system responds to hyperthermia exposure resulting in heat stroke by producing an array of immunological proteins, such as interleukin-6 (IL-6). However, the physiological functions of IL-6 and other cytokines in hyperthermia are poorly understood.
We hypothesized that IL-6 plays a protective role in conditions of heat stroke. To test this, we gave small IL-6 supplements to mice prior to exposing them to hot environments sufficient to induce conditions of heat stroke.
Pretreatment with IL-6 resulted in improved ability to withstand heat exposure in anaesthetized mice, it protected the intestine from injury, reducing the permeability of the intestinal barrier, and it attenuated the release of other cytokines involved in inflammation.
The results support the hypothesis that IL-6 is a ‘physiological stress hormone’ that plays an important role in survival during acute life-threatening conditions such as heat stroke.




Abstract

The role of interleukin-6 (IL-6) in hyperthermia and heat stroke is poorly understood. Plasma IL-6 is elevated following hyperthermia in animals and humans, and IL-6 knockout mice are more intolerant of severe hyperthermia. We evaluated the effect of IL-6 supplementation on organ injury following severe hyperthermia exposure in anaesthetized mice. Two hours prior to hyperthermia, mice were treated with 0.6 μg intraperitoneal IL-6, or identical volumes of saline in controls. Mice were anaesthetized, gavaged with FITC–dextran for measures of gastrointestinal permeability, and exposed to incremental (0.5°C every 30 min) increases in temperature. Heating stopped when maximum core temperature (Tc) of 42.4°C was attained (Tc,max). The mice recovered at room temperature (≈22°C) for 30 or 120 min, at which time plasma and tissues were collected. IL-6-treated mice, on average, required ≈25 min longer to attain Tc,max. Injury and swelling of the villi in the duodenum was present in untreated mice after 30 min of recovery. These changes were blocked by IL-6 treatment. IL-6 also reduced gastrointestinal permeability, assayed by the accumulation of FITC–dextran in plasma. Plasma cytokines were also attenuated in IL-6-treated animals, including significant reductions in TNFα, MCP-1 (CXCL2), RANTES (CCL5) and KC (CCL5). The results demonstrate that IL-6 has a protective influence on the pattern of physiological responses to severe hyperthermia, suggesting that early endogenous expression of IL-6 may provide a protection from the development of organ damage and inflammation.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2014.283416

Protection of intestinal injury during heat stroke in mice by interleukin-6 pretreatment.

Immune modulators called cytokines are released following extreme hyperthermia leading to heat stroke. It is not known whether exercise in hyperthermia, leading to exertional heat stroke, influence...

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.00667.2016

Unique cytokine and chemokine responses to exertional heat stroke in mice

Evidence of increased reactive oxygen species (ROS) production is observed in the circulation during exercise in humans. This is exacerbated at elevated body temperatures and attenuated when normal exercise-induced body temperature elevations are suppressed. Why ROS production during exercise is temperature dependent is entirely unknown. This review covers the human exercise studies to date that provide evidence that oxidant and antioxidant changes observed in the blood during exercise are dependent on temperature and fluid balance. We then address possible mechanisms linking exercise with these variables that include shear stress, effects of hemoconcentration, and signaling pathways involving muscle osmoregulation. Since pathways of muscle osmoregulation are rarely discussed in this context, we provide a brief review of what is currently known and unknown about muscle osmoregulation and how it may be linked to oxidant production in exercise and hyperthermia. Both the circulation and the exercising muscle fibers become concentrated with osmolytes during exercise in the heat, resulting in a competition for available water across the muscle sarcolemma and other tissues. We conclude that though multiple mechanisms may be responsible for the changes in oxidant/antioxidant balance in the blood during exercise, a strong case can be made that a significant component of ROS produced during some forms of exercise reflect requirements of adapting to osmotic challenges, hyperthermia challenges, and loss of circulating fluid volume.

https://www.physiology.org/doi/pdf/10.1152/ajpregu.00395.2015

Hyperthermia, dehydration, and osmotic stress: unconventional sources of exercise-induced reactive oxygen species.

Injury to the intestinal mucosa is a life-threatening problem in a variety of clinical disorders, including hemorrhagic shock, trauma, burn, pancreatitis, and heat stroke. The susceptibility to injury of different regions of intestine in these disorders is not well understood. We compared histological injury across the small intestine in two in vivo mouse models of injury, hemorrhagic shock (30% loss of blood volume) and heat stroke (peak core temperature 42.4°C). In both injury models, areas near the duodenum showed significantly greater mucosal injury and reductions in villus height. To determine if these effects were dependent on circulating factors, experiments were performed on isolated intestinal segments to test for permeability to 4-kDa FITC-dextran. The segments were exposed to hyperthermia (42°C for 90 min), moderate simulated ischemia (Po2 ∼30 Torr, Pco2 ∼60 Torr, pH 7.1), severe ischemia (Po2 ∼20 Torr, Pco2 ∼80 Torr, pH 6.9), or severe hypoxia (Po2 ∼0 Torr, Pco2 ∼35 Torr) for 90 min, and each group was compared with sham controls. All treatments resulted in marked elevations in permeability within segments near the duodenum. In severe hypoxia or hyperthermia, permeability was also moderately elevated in the jejunum and ileum; in moderate or severe ischemia, permeability was unaffected in these regions. The results demonstrate increased susceptibility of proximal regions of the small intestine to acute stress-induced damage, irrespective of circulating factors. The predominant injury in the duodenum may impact the pattern of acute inflammatory responses arising from breach of the intestinal barrier, and such knowledge may be useful for designing therapeutic strategies.

https://www.physiology.org/doi/pdf/10.1152/ajpgi.00166.2013

Michelle A. King

Papers

Biomarkers of multiorgan injury in a preclinical model of exertional heat stroke

Protection of intestinal injury during heat stroke in mice by interleukin-6 pretreatment.

Unique cytokine and chemokine responses to exertional heat stroke in mice

Hyperthermia, dehydration, and osmotic stress: unconventional sources of exercise-induced reactive oxygen species.

Regional susceptibility to stress-induced intestinal injury in the mouse