ovalbumin and Hypothermia

The fact that only some individuals exposed to environmental chemicals develop chemical intolerance raises the possibility that genetic factors could be contributing factors. The present communication summarizes evidence from a genetic animal model of cholinergic supersensitivity that suggests that an abnormal cholinergic system could be one predisposing genetic factor. The Flinders Sensitive Line (FSL) rats were established by selective breeding for increased responses to an organophosphate. It was subsequently found that these FSL rats were also more sensitive to direct-acting muscarinic agonists and had elevated muscarinic receptors compared to the selectively bred parallel group, the Flinders Resistant Line (FRL) rats, or randomly bred control rats. Increased sensitivity to cholinergic agents has also been observed in several human populations, including individuals suffering from chemical intolerance. Indeed, the FSL rats exhibit certain behavioral characteristics such as abnormal sleep, activity, and appetite that are similar to those reported in these human populations. In addition, the FSL rats have been reported to exhibit increased sensitivity to a variety of other chemical agents. Peripheral tissues, such as intestinal and airway smooth muscle, appear to be more sensitive to both cholinergic agonists and an antigen, ovalbumin. Hypothermia, a centrally mediated response, is more pronounced in the FSL rats after nicotine and alcohol, as well as agents that are selective for the dopaminergic and serotonergic systems. In some cases, the increased sensitivity has been detected in the absence of any changes in the receptors with which the drugs interact (dopamine receptors), while receptor changes have been seen in other cases (nicotine receptors). Therefore, there may be multiple mechanisms underlying the multiple chemical sensitivity-chemical intolerance of the FSL rats. An elucidation of these mechanisms may provide useful clues to those involved in chemical intolerance in humans.

Topics: Acetylcholine; Allergens; Animals; Asthma; Cholinergic Agents; Cholinergic Fibers; Cholinesterase Inhibitors; Disease Models, Animal; Environmental Pollutants; Fatigue Syndrome, Chronic; Humans; Hypothermia; Models, Biological; Multiple Chemical Sensitivity; Muscarinic Agonists; Muscle, Smooth; Nicotinic Agonists; Ovalbumin; Pesticides; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Muscarinic; Receptors, Nicotinic; Second Messenger Systems; Serotonin Receptor Agonists; Sleep Wake Disorders; Up-Regulation

Topics: Anaphylaxis; Animals; Body Fluids; Brain Chemistry; Cell Degranulation; Cell Hypoxia; Chymases; Cold Temperature; Female; Hypothermia; Kidney; Mast Cells; Mice; Mice, Inbred C57BL; NAD; Ovalbumin; Oxygen

MicroRNAs (miRNAs) are small, noncoding RNAs that have been shown to play a critical role in normal physiology and disease, such as hematopoietic development and cancer. However, their role in mast-cell function and development is poorly understood. The major objective of this study was to determine how global miRNA expression affects mast-cell physiology. The RNase III endonuclease, Dicer, is required for the processing of pre-miRNAs into mature miRNAs. To investigate the effect of global miRNA depletion on mast cells in vivo, we generated a mast-cell-specific knock out of Dicer in mice. Transgenic mice (Mcpt5-Cre) that express Cre selectively in connective tissue mast cells were crossed with mice carrying the floxed conditional Dicer allele (Dicer fl/fl). Mcpt5-Cre × Dicer fl/fl mice with homozygous Dicer gene deletion in mast cells were found to have a profound mast-cell deficiency with near complete loss of peritoneal, gastrointestinal, and skin mast cells. We examined the in vivo functional consequence of mast-cell-specific Dicer deletion using an immunoglobulin-E-dependent passive systemic anaphylaxis murine model. Immunoglobulin-E-sensitized wild type Mcpt5-Cre × Dicer +/+ and heterozygous Mcpt5-Cre × Dicer fl/+ mice show marked hypothermia with antigen; however, homozygous Mcpt5-Cre × Dicer fl/fl mice were completely unresponsive to antigen challenge. These studies suggest a critical role for Dicer and miRNA expression for establishment of tissue compartments of functional mast cells in vivo.

Topics: Anaphylaxis; Animals; Cell Count; Crosses, Genetic; DEAD-box RNA Helicases; Gene Expression Regulation; Genotype; Humans; Hypothermia; Immunization; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; MicroRNAs; Organ Specificity; Ovalbumin; Peritoneum; Ribonuclease III; Serum Albumin; Skin; Stomach

Systemic anaphylaxis is the most severe form of immediate hypersensitivity reaction. The activation of the complement system occurs during anaphylactic shock. The purpose of this study was to determine in a mouse model whether the lectin pathway of complement activation is involved in anaphylaxis.. To see whether the lectin pathway is involved in anaphylactic shock, serum mannan-binding lectin (MBL) levels were measured after passive anaphylaxis. Also MBL expression and binding to potential ligands were investigated. To determine whether complement or mast cell activation is essential for hypothermia in anaphylactic shock, mouse strains deficient in MBL-A and MBL-C, C1q, factors B and C2, C5, C5aR, or mast cells were tested.. After antigenic challenge a marked drop in body temperature as well as a rapid decrease in serum MBL levels were observed. The decrease of serum MBL levels in shock could not be attributed to MBL binding to immune complexes or tissues, but an interaction of MBL with mast cell-derived proteoglycans was seen. In contrast to mast cell-deficient mice, none of the complement-deficient mouse strains were protected from shock-associated hypothermia.. These results indicate that neither MBL nor activation of the complement cascade is crucial for the induction of anaphylaxis. In contrast mast cell activation is associated with the development of hypothermia and possibly the observed decrease in serum MBL levels.

Topics: Anaphylaxis; Animals; Complement Activation; Enzyme-Linked Immunosorbent Assay; Female; Hypothermia; Immunohistochemistry; Mannose-Binding Lectin; Mast Cells; Mice; Mice, Inbred DBA; Mice, Mutant Strains; Ovalbumin; Polymerase Chain Reaction; Proteoglycans; RNA, Messenger

Following sensitization to ovalbumin (OA), male Wistar rats were pretreated with naloxone (20 mg/kg i.p.) and subjected to antigen challenge (3 mg OA i.p.). Naloxone exacerbated both systemic and intestinal anaphylaxis when injected 10 and 90 min before the antigen challenge. This was evidenced by a more pronounced drop in rectal temperature, higher hematocrit values, and by an enhanced elevation of basal short-circuit current (an indication of the secretory tone of the small intestine studied in Ussing chambers). Pretreatment with an equipotent does of methylnaloxone (200 mg/kg i.p.), a peripherally acting opiate antagonist, exacerbated the indices of intestinal anaphylaxis but had no apparent effect on indices of systemic anaphylaxis. Thus, our data strongly suggest that in the rat, components of the systemic hypersensitivity reaction are mediated through central opioid receptors, whereas the changes in gut function characterizing intestinal anaphylaxis are mediated through peripheral opioid receptors.

Topics: Anaphylaxis; Animals; Biological Transport; Cell Membrane Permeability; Chlorides; Hematocrit; Histamine Release; Hypothermia; Immunization; Intestinal Absorption; Male; Naloxone; Neuroimmunomodulation; Ovalbumin; Oxymorphone; Rats; Rats, Wistar; Receptors, Opioid; Specific Pathogen-Free Organisms; Water