Inflammation, organomegaly, and muscle wasting despite hyperphagia in a mouse model of burn cachexia.

BACKGROUND: Burn injury results in a chronic inflammatory, hypermetabolic, and hypercatabolic state persisting long after initial injury and wound healing. Burn survivors experience a profound and prolonged loss of lean body mass, fat mass, and bone mineral density, associated with significant morbidity and reduced quality of life. Understanding the mechanisms responsible is essential for developing therapies. A complete characterization of the pathophysiology of burn cachexia in a reproducible mouse model was lacking. METHODS: Young adult (12-16 weeks of age) male C57BL/6J mice were given full thickness burns using heated brass plates or sham injury. Food and water intake, organ and muscle weights, and muscle fiber diameters were measured. Body composition was determined by Piximus. Plasma analyte levels were determined by bead array assay. RESULTS: Survival and weight loss were dependent upon burn size. The body weight nadir in burned mice was 14 days, at which time we observed reductions in total body mass, lean carcass mass, individual muscle weights, and muscle fiber cross-sectional area. Muscle loss was associated with increased expression of the muscle ubiquitin ligase, MuRF1. Burned mice also exhibited reduced fat mass and bone mineral density, concomitant with increased liver, spleen, and heart mass. Recovery of initial body weight occurred at 35 days; however, burned mice exhibited hyperphagia and polydipsia out to 80 days. Burned mice had significant increases in serum cytokine, chemokine, and acute phase proteins, consistent with findings in human burn subjects. CONCLUSIONS: This study describes a mouse model that largely mimics human pathophysiology following severe burn injury. These baseline data provide a framework for mouse-based pharmacological and genetic investigation of burn-injury-associated cachexia.

Body surface area prediction in normal, hypermuscular, and obese mice.

BACKGROUND: Accurate determination of body surface area (BSA) in experimental animals is essential for modeling effects of burn injury or drug metabolism. Two-dimensional surface area is related to three-dimensional body volume, which in turn can be estimated from body mass. The Meeh equation relates body surface area to the two-thirds power of body mass, through a constant, k, which must be determined empirically by species and size. We found older values of k overestimated BSA in certain mice; thus we determined empirically k for various strains of normal, obese, and hypermuscular mice. MATERIALS AND METHODS: BSA was computed from digitally scanned pelts and nonlinear regression analysis was used to determine the best-fit k. RESULTS: The empirically determined k for C57BL/6J mice of 9.82 was not significantly different from other inbred and outbred mouse strains of normal body composition. However, mean k of the nearly spheroid, obese lepr(db/db) mice (k = 8.29) was significantly lower than for normals, as were values for dumbbell-shaped, hypermuscular mice with either targeted deletion of the myostatin gene (Mstn) (k = 8.48) or with skeletal muscle specific expression of a dominant negative myostatin receptor (Acvr2b) (k = 8.80). CONCLUSIONS: Hypermuscular and obese mice differ substantially from normals in shape and density, resulting in considerably altered k values. This suggests Meeh constants should be determined empirically for animals of altered body composition. Use of these new, improved Meeh constants will allow greater accuracy in experimental models of burn injury and pharmacokinetics.

Natural resistance, iron and infection: a challenge for clinical medicine.

Natural resistance to infection, which does not depend on antibiotics, is a powerful protective mechanism common to all mankind that has been responsible for the survival of our species during countless millennia in the past. The normal functioning of this complex system of phagocytic cells and tissue fluids is entirely dependent on an extremely low level of free ionic iron (10(-18) M) in tissue fluids. This low-iron environment is maintained by the unsaturated iron-binding proteins transferrin and lactoferrin, which depend on well-oxygenated tissues, where a relatively high oxidation-reduction potential (Eh) and pH are essential for the binding of ferric iron. Freely available iron is derived from iron overload, free haem compounds, or hypoxia in injured tissue leading to a fall in Eh and pH. This can severely damage or abolish normal bactericidal mechanisms in tissue fluids leading to overwhelming growth of bacteria or fungi. The challenge for clinical medicine is to reduce or eliminate the presence of freely available iron in clinical disease. In injured or hypoxic tissue, treatment with hyperbaric oxygen might prove very useful by increasing tissue oxygenation and restoring normal bactericidal mechanisms in tissue fluids, which would be of huge benefit to the patient.

Iron and infection: the heart of the matter.

Bacterial resistance to antibiotics is a major threat to clinical medicine. However, natural resistance to bacterial infection, which does not depend on antibiotics, is a powerful protective mechanism common to all mankind. The availability of iron is the heart of the matter and the successful functioning of these antibacterial systems depends entirely upon an extremely low level of free ionic iron (10(-18) M) in normal tissue fluids. This in turn depends on well-oxygenated tissues where the oxidation-reduction potential (Eh) and pH control the binding of iron by unsaturated transferrin and lactoferrin. Bacterial virulence is greatly enhanced by freely available iron, such as that in fully-saturated transferrin or free haemoglobin. Following trauma a fall in tissue Eh and pH due to ischaemia, plus the reducing powers of bacteria, can make iron in transferrin freely available and abolish the bactericidal properties of tissue fluids with disastrous results for the host. Hyperbaric oxygen is a possible therapeutic measure that could restore normal bactericidal systems in infected tissues by raising the Eh and pH.