2 FARMACI CHE DEPRIMONO L’ATTIVITÀ DEI CENTRI RESPIRATORIAnalgesici narcoticiBarbituriciAntagonisti del recettore istaminergico H1AntidepressiviEtanolo.Benzodiazepine
3 Schematic representation of the innervation of the airways Schematic representation of the innervation of the airways. The figure shows that the vagus nerves supply all parasympathetic and most of the sensory nerve fibres to the airways. Some sensory innervation originates from the dorsal root ganglia and these sensory fibres run with spinal sympathetic nerves.Overview of the innervation of the lung, Current Opinion in Pharmacology, Volume 2, Issue 3, 1 June 2002, Pages Maria G. Belvisi
7 The pathophysiology of asthma The pathophysiology of asthma. Several inflammatory cells are recruited and/or activated in the airways, releasing a variety of inflammatory mediators that have acute effects on the airway (such as bronchoconstriction, plasma leakage, vasodilatation, mucus secretion, sensory nerve activation and cholinergic reflex-induced bronchoconstriction), together with structural changes (remodelling) that include subepithelial fibrosis, increased numbers of blood vessels and mucus-secreting cells, and increased thickness of airway smooth muscle as a result of hyperplasia and hypertrophy.
9 Interactions between tachykinins and eicosanoids following antigen challenge. Antigen (Ag) binding to IgE on mast-cell plasma membranes causes degranulation and release of cysteinyl leukotrienes (cys-LTs) LTC4, LTD4 and LTE4, prostaglandins (PGs) such as PGD2 and PGF2 , thromboxane (TX) A2, and 8-iso-PGF2 , an F2-isoprostane (IP). These eicosanoids cause early bronchoconstriction by interacting with their specific receptors on smooth muscle cells. Prostnoid receptor (P) subtypes are not specified in the figure. The cellular source(s) of IPs is not known. Cys-LT-induced airway contraction is partly a result of increased release of tachykinins such as substance P (SP) and neurokinin A (NKA) from sensory nerves. These neuropeptides play an important role in the late bronchoconstriction and development of airway hyperresponsiveness (AHR) by interacting with tachykinin NK1 and NK2 receptors. Moreover, tachykinins can further stimulate inflammatory cells such as alveolar macrophages to release TXA2 and possibly other eicosanoids, which amplify the effects of the antigen¯antibody interaction. Tachykinins released from non-neuronal cells (e.g. alveolar macrophage and eosinophils) could also play a role. Other inflammatory cells such as eosinophils (not indicated in the figure) might also be involved in this response. The presence of NK2 receptors and the effects of prostanoids on tachykinin-containing nerves requires further clarification.
10 MEDIATORI DEL PROCESSO INFIAMMATORIO RILASCIATI DAI MASTOCITICLASSEMEDIATOREEFFETTOPreformatiIstaminaVasodilatazione, permeabilizzazione vascolare, prurito, tosse, broncocostrizione, rinorreaProteasiVasodilatazione, permeabilizzazione vascolare, broncocostrizioneEparina?Derivati da lipidiLTC4broncocostrizione, Vasodilatazione, permeabilizzazione vascolareLTB4Chemiotassi leucocitariaPGD2Vasodilatazione, permeabilizzazione vascolare, broncocostrizione, secrezione mucosaPAFbroncocostrizione, Chemiotassi leucocitaria
11 (a) Regulatory elements in goblet-cell mucus secretion in rodents and guinea-pigs. Neuronal control of surface epithelial goblet cells regulates mucus secretion directly. Additionally, inflammatory mediators (e.g. from leukocytes) might act on epithelial goblet cells either directly, or indirectly via neuronal mechanisms to influence goblet-cell mucus secretion. (b) Human glandular mucus secretion. Neuronal mechanisms directly regulate mucus secretion from gland cells. Inflammatory mediators (e.g. from leukocytes) might also act on glandular mucous cells either directly, or indirectly via neuronal mechanisms to influence mucus secretion. Similarities in regulation are apparent between human glands and rodent goblet cells. (c) Regulatory elements in human goblet-cell mucus secretion. Neuronal control of surface epithelial goblet cells is essentially absent. Inflammatory mediators (e.g. from leukocytes) act directly on epithelial goblet cells to influence mucus secretion
12 Fig. 2. Innervation of airway mucus-secreting cells Fig. 2. Innervation of airway mucus-secreting cells. This simplified schematic shows the principal neuronal pathways that induce secretion. Cholinergic (parasympathetic) nerves constitute the dominant pathway (red), whereby acetylcholine (ACh) interacts with muscarinic M3 receptors to increase mucus output. Adrenergic (sympathetic) neural control of airway secretion (broken black lines and noradrenaline [NA]) is species-specific and has not been demonstrated in human airways. Blood-borne catecholamines like adrenaline (A) from the adrenal medulla interact with adrenoceptors (Ad) on the secretory cells to increase mucus output. Sensory nerve endings (blue) in the epithelium detect inhaled irritants and relay impulses via sensory (afferent) pathways to the central nervous system (CNS) to initiate reflex secretion (e.g. via cholinergic nerves). Axonal neurotransmission via collateral sensory¯efferent pathways leads to release of sensory neuropeptides including SP and NKA, which interact with tachykinin NK1 receptors to increase secretion. The diagram does not illustrate how neuronal pathways that contain other neuropeptides (e.g. VIP), or NOS (which produces NO) interact with these main motor pathways to regulate the magnitude of secretion.
13 Development of goblet-cell metaplasia Development of goblet-cell metaplasia. Recruitment and activation of leukocytes leads to the phenotypic conversion of non-goblet cells to goblet cells in a process termed goblet-cell metaplasia. Such established mechanisms of increased mucus production are indicated by black arrows. Blue arrows represent the hypothesis that leukocyte-independent generation of goblet-cell metaplasia might be possible as a result of direct activation of epithelial cells by, for example, lipopolysaccharide.
15 Molecular mechanisms of action of bronchodilators Molecular mechanisms of action of bronchodilators. Activation of 2 adrenoceptors, vasoactive intestinal peptide (VIP) and prostaglandin E2 (PGE2) receptors results in activation of adenylyl cyclase (AC) via a stimulatory G-protein (Gs) and an increase in cAMP concentration. This activates protein kinase A (PKA), which then phosphorylates several target proteins, resulting in the opening of calcium-activated potassium channels (KCa) or maxi-K channels, decreased phosphoinositide (PI) hydrolysis, increased Na+/K+ ATPase and decreased myosin light chain kinase (MLCK) activity, which leads to relaxation of airway smooth muscle. In addition, 2-adrenoceptors can be coupled directly via Gs to KCa. cAMP is broken down by phosphodiesterases (PDE), which are inhibited by theophylline and selective PDE3 inhibitors, and which could therefore be potential asthma therapies.
16 Muscarinic receptors in the lung Muscarinic receptors in the lung. Vagal parasympathetic nerves from the brain terminate at peripheral ganglia in the lungs. Acetylcholine (ACh) released here acts via M1 muscarinic receptors on postganglionic, nonmyelinated efferent nerves that innervate the submucosal glands and ASM. Presynaptic M2 muscarinic receptors are inhibitory autoreceptors on the postganglionic nerves. ACh released onto ASM causes bronchoconstriction via the M3 muscarinic receptors and mucus secretion via the M1 and M3 muscarinic receptors. Selective muscarinic receptor antagonists for airway diseases, Current Opinion in Pharmacology, Volume 1, Issue 3, 1 June 2001, Pages Ann M. Lee, David B. Jacoby and Allison D. Fryer
19 Possible actions of 5-HT on human airway smooth muscle Possible actions of 5-HT on human airway smooth muscle. In humans, 5-HT is concentrated in platelets and is released when platelets aggregate. 5-HT that is released from platelets can cause both constriction and relaxation of bronchioles and bronchi, depending on the concentration used. The control of human airway function appears to be dependent on four 5-HT receptor subtypes (5-HT1A, 5-HT2A, 5-HT3 and 5-HT7). In particular, 5-HT activates 5-HT2A and 5-HT1A receptors on airway smooth muscle to cause muscle constriction and relaxation, respectively. In addition, some of the released 5-HT acts on presynaptic 5-HT3 and 5-HT7 receptors at the parasympathetic nerve terminal to facilitate release of acetylcholine (ACh).
20 Sites of action of 5-HT modifiers tested in, or proposed for, asthmatic patients. It is possible to reduce the level of 5-HT in the lung by either interfering with the 5-HT transporter and thus inhibiting the efflux of 5-HT (e.g. dexfenfluramine and citalopram), or increasing reuptake of 5-HT by platelets (e.g. tianeptine). Reduction in postganglionic facilitation of cholinergic neurotransmission might be possible by inhibition of prejunctional 5-HT3 or 5-HT7 receptors by ondansetron, granisetron and tropisetron or epinastine and methysergide, respectively, and thus lead to modulation of airway hyperresponsiveness (AHR). Inhibition of 5-HT2A receptors with ketanserin or droperidol, or activation of 5-HT1A receptors with urapidil or 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] induces a weak bronchodilation.
28 Fig. 1. Leukotriene pathways Fig. 1. Leukotriene pathways. (a) Arachidonic acid is liberated from membrane phospholipid via the action of cytoplasmic phospholipase A2 (cPLA2), a process that can be inhibited by steroids. (b) From arachidonic acid, LTA4 is generated via 5-lipoxygenase (5-LO) (which is inhibited by zileuton) and its activating protein FLAP (which is inhibited by MK-886 and BAY x1005). (c) Also generated from arachidonic acid, by the action of the prostaglandin endoperoxide H synthases (PGHS 1 and 2) and cyclooxygenase (COX), are the prostaglandins (PGs) and thromboxanes (TXs); this step is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. LTA4 can (d) spontaneously or catalytically hydrolyze to LTB4, or (e) can be conjugated with glutathione (GSH) to form the first of the cLTs, LTC4. (f) Stepwise hydrolysis of the peptide residues of LTC4 produces LTD4 and LTE4. (g) These compounds bind to and activate the cys-LT1-receptor (cys-LT1-R) to produce the physiological effects of the cLTs. (h) The lukasts interfere with binding and activation of the cys-LT1-receptor.Anti-leukotrienes for asthma, Current Opinion in Pharmacology, Volume 1, Issue 3, 1 June 2001, Pages William J. Calhoun
30 INIBIZIONE DELLA5-LIPOSSIGENASIANTAGONISMO DEI RECETTORIPER I LEUCOTRIENI
31 Fig. 1. Putative signaling pathways that regulate cytokine-induced synthetic responses in ASM cells. (a) cAMP-mobilizing agents inhibit cytokine-induced expression of chemokines and CAMs, (b) possibly through attenuation of NF B and MAP kinase signaling. Cytokine-induced NF- B activation in human ASM is corticosteroid-insensitive. However, expression of some, but not all, genes is inhibited by corticosteroids (see text for details). AP-1, activator protein 1; CRE, cAMP response element; ERK: extracellular signal-regulated kinase; GR, glucocorticoid receptor; GRE, glucocorticoid response element; JNK, c-Jun N-terminal kinase; PDE-IV, phosphodiesterase type IV, PKA, cAMP-dependant protein kinase. '?' indicates putative interactions.Airway smooth muscle as an immunomodulatory cell: a new target for pharmacotherapy?, Current Opinion in Pharmacology, Volume 1, Issue 3, 1 June 2001, Pages Aili L Lazaar and Reynold A Panettieri, Jr SummaryPlus | Full Text + Links | PDF (687 K)
32 There are several strategies for inhibiting pro-inflammatory cytokines in asthma. These include inhibition of cytokine synthesis (for example, corticosteroids), inhibition of transcription factors regulating cytokine expression (for example, calcineurin inhibitors or decoy oligonucleotides), inhibition of secreted cytokines with blocking antibodies (for example, anti-interleukin (IL)-5 antibody) or soluble receptors (for example, soluble IL-4 receptors), blocking cytokine receptors (for example, chemokine receptor antagonists), blocking signal-transduction pathways (for example, p38 mitogen-activated protein kinase inhibitors) or transcription factors activated by cytokines (for example, STAT6 inhibitors).
34 Airway pathology in COPD Airway pathology in COPD. The airway in normal subjects is distended by alveolar attachments. a | In chronic obstructive pulmonary disease (COPD), these attachments are reduced, which contributes to airway closure. Peripheral airways are also obstructed by b | inflammation and c | mucus obstruction.
35 Management of chronic obstructive pulmonary disease Management of chronic obstructive pulmonary disease. Summary of progressive treatment approaches.
36 Targets for COPD therapy that are based on current understanding of the inflammatory mechanisms. Cigarette smoke (and other irritants) activate macrophages in the respiratory tract that release neutrophil chemotactic factors, including interleukin-8 (IL-8) and leukotriene B4 (LTB4). These cells then release proteases that break down connective tissue in the lung parenchyma, resulting in emphysema, and also stimulate mucus hypersecretion. These enzymes are normally counteracted by protease inhibitors, including 1-antitrypsin, secretory leukoprotease inhibitor (SLPI) and tissue inhibitor of matrix metalloproteinases (TIMPs). Cytotoxic T cells (CD8+) might also be involved in the inflammatory cascade.
37 Highly schematic representation of the neural pathways controlling airway function. (a) Vagal preganglionic parasympathetic neurons originating in the nA and dmnx in the brainstem provide the primary innervation to the airways. Two distinct parasympathetic pathways exist, differing with respect to their effect on airway smooth-muscle tone: (b) parasympathetic cholinergic nerves contain and release acetylcholine (ACh); (c) conversely, parasympathetic non-cholinergic nerves contain and release nitric oxide (NO) and vasoactive intestinal peptide (VIP). In addition, nerves derived from the spinal cord (SC) include (d) preganglionic fibres projecting to sympathetic neurons containing noradrenalin (NA) and neuropeptide Y (NPY), which produce vasoconstriction and (e) respiratory motor neurons innervating the respiratory muscles of the thorax. Respiratory motorneurons innervating the respiratory muscles also originate in the spinal cord. Sympathetic nerves do not seem to innervate airway smooth muscle in humans but in other species they directly innervate airway smooth muscle and mediate bronchodilatation (see  for review). Parasympathetic preganglionic (and probably sympathetic and somatic) nerve activity is reflexly regulated by afferent nerve input to the nTS: (f) activation of airway RARs (rapidly adapting mechanoceptors) and C-fibers increases (+) both cholinergic and non-cholinergic nerve activity, whereas (g) chemoreceptors and SARs (slowly adapting mechanoceptors) regulate (+ and -) cholinergic nerve activity only . The central pathways from airway-related neurons in the nTS to those in the nA and dmnX (and SC) are not fully described. Different patterns indicate neurons with different functions.
39 Illustration of the different components thought to contribute towards BHR. Changes include (a) reduced epithelium barrier function ; (b) airway wall remodelling (increased thickness) , increase in airway smooth-muscle function ; (c) increase in vascular reactivity ; (d) increased activity of inflammatory cells [20 and 21]; and (e) dysfunction of muscarinic M2 receptors located on postganglionic parasympathetic fibre terminals . It is likely that signals received from the different inputs are necessary for the full expression of BHR. Airway afferent nerves could act as a focal point linking the external environment to airway smooth muscle via the central nervous system (CNS). Recently, it has been demonstrated that the excitability of neurones within the nucleus tractus solitarius ¯¯ a key site where sensory input is integrated and motor reflex responses initiated ¯¯ is increased following antigen challenge in allergic monkeys. This supports a role for central sensitisation in BHR .
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