Homeostasis 3. Árpád Dobolyi. Laboratory of Molecular and Systems Neurobiology, Department of Physiology and Neurobiology, Eötvös Loránd University

Transcription

1 Homeostasis 3 Árpád Dobolyi Laboratory of Molecular and Systems Neurobiology, Department of Physiology and Neurobiology, Eötvös Loránd University

2 Outline of the lecture 1. Internal environment of living organisms 2. Homeostatic regulations the endocrine system 3. Examples of homeostatic regulations not requiring the nervous system 4. Homeostatic regulations nervous system 5. Examples of regulations involving the brain Water balance Body temperature regulation 6. Homeostatic regulations immune system 7. The role of the nervous system in immune regulations

3 Heat produced by basal metabolism Energy produced by basal metablism leaves the body in the form of heat. It depends on the size of the animals: - Heat produced by bigger animals is larger - Heat produced per body weight decreases with the size of the animal Rubner s surface area law: heat produced by the basal metabolism of animals is proportional with their surface area rather than their body weight. More precisely: Heat produced by basal metabolism is proportional to W 0.75, where W is the body weight. Thus, heat production is 290 KJ/W 0.75, and does not depend on the individual or the species.

4 Factors determining heat balance of animals Animals with constant body temperature thrive for heat balance: Heat loss = heat taken from the environment + heat produced by the body Red color: controlability

5 Body temperature control In response to small alterations from set point body temperature, animals first change the circulation of the skin: If ambient temperature decreases, skin arterioles contract thereby decreasing heat dissipation If ambient temperature increases, skin arterioles dilatate thereby increasing heat dissipation

6 Body temperature control 2. In response to larger alterations from set point body temperature: A. In cold environment Heat production by the brown adipose tissue is activated Muscle contraction can further increase heat production (shivering) Activation of thyroid hormone production increases metabolism by enhancing cellular oxidation Appropriate behavioral changes B. In warm environment Enhanced ventillation of the lung Sweating starts, water evaporates from the skin Appropriate behavioral changes

7 Mechanism of heat production in brown adipose tissue If the inner membrane of mitochondrium leaks H-ions then heat is produced instead of ATP

8 Body temperature control 3. If previous measures were insufficient and body temperature alteration is life-threatening: A. In cold environment Due to the activation of stress axis, cellular metabolism is further increased B. In hot environment Heart frequency and blood circulation increases

9 Body temperature control 4. Slower adaptations to changes of long-time alterations of ambient temperature: 1. Alterations of thermal insulation: - adiposity depos build up - Changes of outer integument (e.g. seasonal changes of hair, feather) 2. Appropriate behavioral changes

10 Temperature receptors: transients receptor potential (TRP) channels Etain A. Tansey, and Christopher D. Johnson Advan in Physiol Edu 2015;39:

11 Temperature receptors (TRP channels) are located on free (or bare) nerve terminals in the skin Thin myelinated (Aδ) or unmyelinated axons (C)

12 Termination of heatsensitive primary afferents in the spinal cord A A A C A termosensitive (cold) fibers termination: lamina I lamina IIa lamina V C termosensitive (warm) fibers termination : lamina IIb

13 Neuronal pathways carrying temperature information Pathways of heat sensation and heat localization (only ascending) - spinothalamic tract - trigeminothalamic tract Thermoregulatory pathways - ascending and descending Pathways of thermal stress (only descending)

14 The ventral posterolateral nucleus of the thalamus (VPL) relays sensory inputs from the body to the cerebral cortex

15 Thermoregulatory pathways DH: dorsal horn of spinal cord LPB: lateral parabrachial nucleus POA: preoptikus terület MnPO: median preoptic nucleus MPA: medial preoptic area CVC: cutaneous vasoconstrictor W-S: warm-sensitive DMH: dorsomedial hypothalamic nucleus rrpa: rostral raphe pallidus VH: ventral horn of spinal cord IML: intermediolateral cell column BAT: brown adipose tissue

16 Lateral parabrachial nucleus (LPBN) scp: superior cerebellar peduncle = brachium superior

17 Heat-sensitive neurons in the preoptic region of the hypothalamus : Cells reacting to central and peripheral change of temperature

18 Summation of peripheral and central input on heatsensitive neurons of the medial preoptic area a, b: activation of peripheral warm-sensitive receptors c-d: activation of central warm-sensitive receptors e: activation of central cold-sensitive receptors

19 Thermoregulatory patyways DH: dorsal horn of spinal cord LPB: lateral parabrachial nucleus POA: preoptikus terület MnPO: median preoptic nucleus MPA: medial preoptic area CVC: cutaneous vasoconstrictor W-S: warm-sensitive DMH: dorsomedial hypothalamic nucleus rrpa: rostral raphe pallidus VH: ventral horn of spinal cord IML: intermediolateral cell column BAT: brown adipose tissue

20 Location of the dorsomedial nucleus in the hypothalamus and the raphe pallidus in the medulla

21 Body temperature control 2. In response to larger alterations from set point body temperature: A. In cold environment Heat production by the brown adipose tissue is activated Muscle contraction can further increase heat production (shivering) Activation of thyroid hormone production increases metabolism by enhancing cellular oxidation Appropriate behavioral changes B. In warm environment neuronal pathways are not known Enhanced ventillation of the lung Sweating starts, water evaporates from the skin Appropriate behavioral changes

22 Neuroendocrine and descending thermoregulatoy pathways controlling the secretion of thyroid hormones

23 Body temperature control 3. If previous measures were insufficient and body temperature alteration is life-threatening: A. In cold environment Due to the activation of stress axis, cellular metabolism is further increased B. In hot environment Heart frequency and blood circulation increases

24 Pathways of heat stress

25 When the set point of body temperature regulation in increased: fever The effects of fever: Proliferation of bacteria and viruses decreases T cell proliferation increases Lymphocyte transformation is enhanced Gamma-interferon production is elevated

26 Pyrogenes Any substance that leads to fever Endogenous pyrogenes: - Some cytokines produced by macrophages: Interleukin 1 (α és β), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNFα) Exogenous pyrogenes: - Any inflammatory reaction that activates macrophages. Bacterial lipopolysaccharide (LPS) is particularly effective in inducing fever Mechanism of action: Pyrogenes result in the production of prostaglandin E2-t (PGE2). PGE2 acts on the hypothalamus to increase the set point. Consequently, the body produces heat and decreases its dissipation.

27 pirogene citokynes Humoral and neuronal hypothesis of fever IL-1 TNF- IL-6 Endothel / microglia PGE2 Prosztaglandin E receptor 3 in preoptic neuros C5a Thermogenesis Het loss (vasokonstriction a bőrben) Dorsomedial hypothalamus (DMH)

28 Synthesis of Prosta- glandin E2 (PGE2) From arachidonic acid Using the following enzymes: phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), prostaglandin E2 synthase Pyrogenes stimulate the enzymes thereby inducing PGE2 synthesis Anti-fever drugs inhibit these enzymes

29 Location of the action of PGE2 within the thermoregulatory pathway Tr. spinothalamicus

30 Outline of the lecture 1. Internal environment of living organisms 2. Homeostatic regulations the endocrine system 3. Examples of homeostatic regulations not requiring the nervous system 4. Homeostatic regulations nervous system 5. Examples of regulations involving the brain Water balance Body temperature regulation 6. Homeostatic regulations immune system 7. The role of the nervous system in immune regulations

31 Immune system Function Defense against tissue damage: Bacterial or viral infection, other pathogens Ischemic, traumatic damage Bleeding Tumor cells Components Barriers: skin, mucose, lung, blood-brain barrier Innate (or natural) immune system Adaptive immune system

32 Comparison of innate and adaptive immune systems Innate immune system: inflammatory processes Not antigen-specific Does not have a threshold Works immediately Has no memory Linearly amplified Adaptive immune system: Antigen-specific Does have a threshold Works with a latency Does have a memory Exponentially amplified

33 AFR 33

34 Inflammatory processes can be divided into 2 steps Step 1: inflammation Immediate Step 2: acute phase reaction (APR) Starts with a latency Local Systemal Without threshold Goal: separation and elimination of damages tissue, regeneration Above threshold Goal: maintain inflammation but also prevent its spreading

35 Initiation (0-6 hours) Bleeding Bacteria Necrosis Virus-infected cell Thrombocyte activation Complement activation Phagocyte activation IL-1 C5a C3a ROI TNF-, IL-1 lipids IL: interleukin; ROI: reaktíve oxygen intermedier, TNF: tumor nekrosis factor

36 Machanisms how bacteria can activate phagocytes Receptors on the surface of phagocytes:: 1. Pattern recognition receptors E.g. Lipopolysaccharid (LPS; a bacterial endotoxin) receptor: CD14(+TLR4) 2. Receptors of the complement system 3. IgG receptors Phagocytes are resident macrophages and arriving granulocytes. Their response to activation: 1. Phagocyte bacteria 2. Production of cytokines

37 Cytokines produced by macrophages and their functions Fülöp AK

38 Mast cell activation results in: 1. degranulation 2. lipid mediators 3. cytokine production Consequences: - Vasodilatation - Increase of tissue permeability - Pain - Activation of additional cells!!! Fülöp AK

39 Vasodilatory effect of histamine

40 Leukocyte infiltration to the site of inflammation Resting State Inflammatory Stimulus Leukocyte Vessel Lumen Inactive Integrin Selectin Counter-receptor Rolling Adhesion Activated Integrin Firm Adhesion Transendothelial Migration Selectin Selectin Expression VCAM Endothelial Cell Subendothelial Matrix

41 Cytokine receptors

42 Signal transduction of IL-1

43 Progression (6-12 hours) Inflammation Acute phase reaction (APR) Early mediators Targets: Phagocytes, endothel, fibroblast, mast cell, keratinocyte, T H 2 Systemic cytokines: TNF, IL-1, IL-6 INFg Adaptive response Liver Bone marrow Adipose tissue CNS Production of proteins Leukocytosis Lipid mobilisation Antiinflammation

44 Outline of the lecture 1. Internal environment of living organisms 2. Homeostatic regulations the endocrine system 3. Examples of homeostatic regulations not requiring the nervous system 4. Homeostatic regulations nervous system 5. Examples of regulations involving the brain Water balance Body temperature regulation 6. Homeostatic regulations immune system 7. The role of the nervous system in immune regulations

45 Acute phase reaction of the central nervous system Systemic cytokines activate the hypothalamus Systemic inhibition of the immune system HPA axis Vegetative nervous system Fever Behavioral effects: No appetite Drowsiness Lack of exploratory and sexual behaviors

46 Relationship of the immune system with the HPA (Hypothalamic-Pituitary-Adrenal) axis Cytokine Hypothalamus Pituitary gland Adrenal gland Immune system IL1, IL6, TNF, INFg CRH (Corticotropin Releasing Hormone) ACTH (Adrenocorticotropic Hormone) Glucocorticoid

47 Paraventricular nucleus in the anterior hypothalamic region

48 Paraventricular hypothalamic nucleus

49 Corticotropin-releasing hormon (CRH)-expressing neurons in the PVN

50 Initiation of CNS acute phase reaction: activation of PVN neurons by IL-1 as compared to other stressors Paraventricular nucleus (PVN) c-fos immunolabeling

51 Anti-inflammatory actions of corticosteroids Activity Effect IL-1, TNF, GM-CSF, IL-3, IL-4. IL-5, IL-8 NOS Foszfolipase A2 Ciklooxygenase2 Adhesion molecules Inflammation (mediated by cytokines) NO Prostaglandins, leukotriens Reduced migration Induction of endonucleases Apoptosis (limfocytes, leukocytes)

52 The effect of glucocorticoids on the number of leukocytes Sejt/mm 3 10,000-4,000-2, Neutrophil granulocytes Lymphocytes Eozinophils Monocytes Basophils 6 h 12 h 24 h

53 Immunosuppression therapy To eliminate unwanted immune response: - Allergy - Autoimmune diseases - Organ transplant a, Antigene-specific immune suppression selective tolerance b, Not-antigene- specific Corticosteroids (in supraphysiological, pharmacological doses) CY-A, FK 506, Rapamycin (T cell proliferation inhibitor) Radiation therapy Cytostatics

54 Natural and artificial glococorticoids Synthetic products: CH 2 OH CH 2 OH Cortisol OH C=O OH O C=O OH Cortizon O O CH 2 OH CH 2 OH Prednizolon C=O OH O C=O OH Prednizon O O (4x more effective than Cortizon)

55 Anti-inflammatory mechanism of glucocorticoids GRE: glucocorticoid receptor element

56 Sites of action of cytokines in the CNS - Through circumventricular organs and also through viscerosensory nerves - It may depend on the type of mediator and its concentration

57 Circumventricular organs humoral inputs

58 The effect of IL-1 on neuronal activation (c-fos expression) in different brain areas

59 Activity of the vagal nerve in response to IL-1 injection IL-1

60 The role of nociceptive sensory system in inflammation Tryptase released by mast cells stimulates nociceptive sensory terminals, which contributes to the activation of HPA axis. In additon: Substance P is released from the sensory terminals upon inflammation G-protein coupled receptor of substance P is present in macrophages, through which substance P increases inflammation

61 Innervation of the immune system

62 Hypothalamo-spinal tract and other descending pathways regulating vegetative functions

63 The effect of the sympathetic nervous system on the immune system Preganglionic neuron Ach Postganglionic neuron Nikotinic receptor Adrenerg receptor Target organ Noradrenaline Macrophages and lymphocytes possess beta 2 adrenerg receptors, which inhibit their actions

64 Additional effects of the sympathetic nervous system on inflammation - In additon to noradrenaline, dopamine and neuropeptide Y are also released from sympathetic terminals - Immune cells have receptors for these modulators as well, through which they inhibit their migration, activation and proliferation, which all contribute to the localization of inflammation

65 Neuromodulation of inflammation 1. sensory terminal (stimulatory) 2. sympath. (inhibitory) 3. parasymp. (inhibitory) Fülöp AK 2010

66 Acute phase reaction of the central nervous system Systemic cytokines activate the hypothalamus Systemic inhibition of the immune system HPA axis Vegetative nervous system Fever Behavioral effects: No appetite Drowsiness Lack of exploratory and sexual behaviors

67 Systemic inflammatory mediators reduce appetite by acting on hypothalamic food intake regulatory neurons

68 Additional effect of inflammatory hormones on energy homeostasis LPL: Lipoprotein lipase, NF: nuclear factor

69 Immune activation produces sickness behaviors, symptomes that resemble to depression

70 Thank you for your attention!