Device and method for inhibiting release of pro-inflammatory mediator

Abstract

Stimulation of one or more neurons of the sympathetic nervous system, including the splenic nerve, to attenuate an immune response, including an inflammatory immune response, is discussed. Devices and systems to stimulate the sympathetic nervous system to attenuate an immune response are also discussed. Devices discussed include pulse generators and drug pumps. Systems are described as optionally having one or more sensors and operator instructions. In specific examples, stimulation of the splenic nerve of pigs with a pulse generator is shown to be safe and effective in attenuating a lipopolysaccharide-induced immune response.

1 . A method for inhibiting the release of a proinflammatory mediator from a mammalian cell, the method comprising stimulating a sympathetic neuron of a mammalian subject in an amount effective to inhibit the release of the proinflammatory mediator.  
   
   
       2 . The method of  claim 1 , wherein the stimulating comprises applying an electrical pulse to the neuron.  
   
   
       3 . The method of  claim 2 , wherein the electrical pulse is applied by a pulse generator.  
   
   
       4 . The method of  claim 3 , wherein the pulse generator is an implantable pulse generator.  
   
   
       5 . The method of  claim 2 , wherein a plurality of electrical pulses is applied to the neuron.  
   
   
       6 . The method of  claim 1 , wherein the sympathetic nerve is the splenic nerve.  
   
   
       7 . The method of  claim 6 , wherein stimulating the splenic nerve comprises applying a stimulation signal to the splenic nerve.  
   
   
       8 . The method of  claim 6 , wherein the stimulation signal is applied to a splenic neurovascular bundle, a periarterial splenic nerve, a substantially fully dissected spelnic nerve or nerve bundles, splenic peritoneum, splenic tissue, celiac plexus surrounding the celiac artery, celiac ganglia, aorticorenal ganglia, greater thoracic splanchnic nerves, lesser thoracic splanchnic nerves, least thoracic splanchinc nerves, lower thoracic sympathetic trunk ganglia, upper lumbar sympathetic trunk ganglia, preganglionic sympathetic fibers, preganglionic sympathetic fibers of T8 -L2, sympathetic trunk ganglia of T8-L2, white ramus communicans of T8-L2, gray ramus communicans of T8-L2, spinal ganglia of T8-L2, ventral root of T8-L2, pregagnglionic sympathetic fibers of T9, sympathetic trunk ganglion of T9, white ramus communicans of T9, gray ramus communicans of T9, spinal ganglion of T9, ventral root of T9, or a combination thereof.  
   
   
       9 . The method of  claim 8 , wherein the stimulation signal comprises an electrical pulse.  
   
   
       10 . The method of  claim 7 , wherein the stimulation signal comprises an electrical pulse.  
   
   
       11 . The method of  claim 10 , wherein the electrical pulse is applied by a pulse generator.  
   
   
       12 . The method of  claim 11 , wherein the pulse generator is an implantable pulse generator.  
   
   
       13 . The method of  claim 11 , wherein a plurality of electrical pulses is applied to the neuron.  
   
   
       14 . The method of  claim 1 , wherein the proinflammatory mediator is a pro-inflammatory cytokine.  
   
   
       15 . The method of  claim 14 , wherein the cytokine is selected from the group consisting of tumor necrosis factor alpha (TNFα); interleukin (IL)-1α; IL-1β; IL-2; IL-5; IL-6; IL-8; IL-15; IL-18; interferon (IFN-γ); platelet-activating factor (PAF); Thromboxane; soluble adhesion molecules; vasoactive neuropeptides; phospholipase A2; Plasminogen activator inhibitor (PAI-1); Free radical generation; Neopterin; CD 14 ; prostacyclin; Neutrophil elastase; Protein kinase; Monocyte chemotactic proteins  1  and  2  (MCP-1, MCP-2); macrophage migration inhibitory factor (MIF); and high mobility group box protein  1  (HMGB-1).  
   
   
       16 . The method of  claim 14 , wherein the proinflammatory cytokine is selected from the group consisting of TNF-α; HMGB-1; IL-1; and IL-6.  
   
   
       17 . The method of  claim 14 , wherein the proinflammatory cytokine is TNF-α.  
   
   
       18 . The method of  claim 1 , wherein the pro-inflammatory mediator is a chemokine.  
   
   
       19 . The method of  claim 1 , wherein the cell is in a patient suffering from, or at risk for, a disease or disorder mediated by an inflammatory cytokine cascade.  
   
   
       20 . The method of  claim 19 , wherein the disease or disorder is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, pseudomembranous colitis, acute ulcerative colitis, chronic ulcerative colitis and ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, nosicomial infection, Crohn's disease, inflammatory bowl disease, enteritis, Whipple's disease, diabetes, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pelvic inflammatory disease, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, urticaria, warts, wheals, vasulitis, cardiovascular disease, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, rheumatoid arthritis, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillane-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, Sjogren's syndrome, myasthenia gravis, thryoiditis, systemic lupus erythematosus, lupus erythematosus, Addison's disease, pernicious anemia, Goodpasture's syndrome, Behcets's syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Type I diabetes, ankylosing spondylitis, spinal cord injury, Retier's syndrome, Graves disease, and Hodgkins disease.  
   
   
       21 . The method of  claim 20 , wherein the disease or disorder is selected from the group consisting of endotoxic shock, appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, inflammatory bowl disease, acute ulcerative colitis, chronic ulcerative colitis, ischemic colitis, hepatitis, nosicomial infection, Crohn's disease, diabetes, asthma, allergy, anaphylactic shock, arteriosclerosis, organ ischemia, reperfusion injury, organ necrosis, sepsis, septicemia, cachexia, septic abortion, disseminated bacteremia, burns, rheumatoid arthritis, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, cardiovascular disease, multiple sclerosis, diabetes, spinal cord injury, allograft rejection and graft-versus-host disease.  
   
   
       22 . The method of  claim 20 , wherein the disease or disorder is endotoxic shock.  
   
   
       23 . The method of  claim 1 , wherein a ganglion is stimulated.  
   
   
       24 . The method of  claim 1 , wherein a postganglionic neuron is stimulated.  
   
   
       25 . The method of  claim 1 , wherein a peripheral tissue or organ served by the splenic nerve is stimulated directly.  
   
   
       26 . The method of  claim 1 , further comprising stimulating a vagusnerve  
   
   
       27 . A method of inhibiting an inflammatory cytokine cascade in a patient, comprising: 
 stimulating a sympathetic neuron in the patient in an amount sufficient to inhibit the inflammatory cytokine cascade,    wherein the patient is suffering from, or at risk for, a disease or disorder mediated by the inflammatory cytokine cascade.    
   
   
       28 . The method of  claim 27 , wherein the sympathetic nerve is stimulated electrically.  
   
   
       29 . The method of  claim 27 , wherein a ganglion is stimulated.  
   
   
       30 . The method of  claim 27 , wherein a postganglionic neuron is stimulated.  
   
   
       31 . The method of  claim 27 , wherein the splenic nerve is stimulated.  
   
   
       32 . The method of  claim 27 , wherein a peripheral tissue or organ served by the splenic nerve is stimulated directly.  
   
   
       33 . The method of  claim 27 , further comprising stimulating the patient's vagus nerve.  
   
   
       34 . The method of  claim 27 , wherein the disease or disorder is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, pseudomembranous colitis, acute ulcerative colitis, chronic ulcerative colitis and ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, nosicomial infection, Crohn's disease, inflammatory bowl disease, enteritis, Whipple's disease, diabetes, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pelvic inflammatory disease, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, urticaria, warts, wheals, vasulitis, cardiovascular disease, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, rheumatoid arthritis, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillane-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, Sjogren's syndrome, myasthenia gravis, thryoiditis, systemic lupus erythematosus, lupus erythematosus, Addison's disease, pernicious anemia, Goodpasture's syndrome, Behcets's syndrome, allograft rejection, graft-versus-host disease, Type I diabetes, ankylosing spondylitis, Berger's disease, Type I diabetes, ankylosing spondylitis, spinal cord injury, Retier's syndrome, Graves disease, and Hodgkins disease.  
   
   
       35 . The method of  claim 27 , wherein the disease or disorder is selected from the group consisting of endotoxic shock, appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, inflammatory bowl disease, acute ulcerative colitis, chronic ulcerative colitis, ischemic colitis, hepatitis, nosicomial infection, Crohn's disease, diabetes, asthma, allergy, anaphylactic shock, arteriosclerosis, organ ischemia, reperfusion injury, organ necrosis, sepsis, septicemia, cachexia, septic abortion, disseminated bacteremia, burns, rheumatoid arthritis, Alzheimer's disease, coeliac disease, congestive heart failure, adult respiratory distress syndrome, cardiovascular disease, multiple sclerosis, diabetes, spinal cord injury, allograft rejection and graft-versus-host disease.  
   
   
       36 . The method of  claim 34 , wherein the disease or disorder is endotoxic shock.  
   
   
       37 . The method of  claim 27 , wherein the disease or disorder is appendicitis.  
   
   
       38 . The method of  claim 27 , wherein the disease or disorder is selected from the group consisting of peptic, gastric and duodenal ulcers.  
   
   
       39 . The method of  claim 27 , wherein the disease or disorder is peritonitis.  
   
   
       40 . The method of  claim 27 , wherein the disease or disorder is pancreatitis.  
   
   
       41 . The method of  claim 27 , wherein the disease or disorder is hepatitis.  
   
   
       42 . The method of  claim 27 , wherein the disease or disorder is asthma.  
   
   
       43 . The method of  claim 27 , wherein the disease or disorder is allergy.  
   
   
       44 . The method of  claim 27 , wherein the disease or disorder is anaphylactic shock.  
   
   
       45 . The method of  claim 27 , wherein the disease or disorder is organ ischemia.  
   
   
       46 . The method of  claim 27 , wherein die disease or disorder is reperfusion injury.  
   
   
       47 . The method of  claim 27 , wherein the disease or disorder is inflammatory bowl disease.  
   
   
       48 . The method of  claim 27 , wherein the disease or disorder is sepsis.  
   
   
       49 . The method of  claim 27 , wherein the disease or disorder is septicemia.  
   
   
       50 . The method of  claim 27 , wherein the disease or disorder is cachexia.  
   
   
       51 . The method of  claim 27 , wherein the disease or disorder is septic abortion.  
   
   
       52 . The method of  claim 27 , wherein the disease or disorder is disseminated bacteremia.  
   
   
       53 . The method of  claim 27 , wherein the disease or disorder is burns.  
   
   
       54 . The method of  claim 27 , wherein the disease or disorder is coeliac disease.  
   
   
       55 . The method of  claim 27 , wherein the disease or disorder is congestive heart failure.  
   
   
       56 . The method of  claim 27 , wherein the disease or disorder is adult respiratory distress syndrome.  
   
   
       57 . The method of  claim 27 , wherein the disease is cardiovascular disease.  
   
   
       58 . The method of  claim 27 , wherein the disease or disorder is Rheumatoid arthritis.  
   
   
       59 . The method of  claim 27 , wherein the disease or disorder is spinal cord injury.  
   
   
       60 . The method of  claim 27 , wherein the disease or disorder is arterioscelerosis.  
   
   
       61 . The method of  claim 27 , wherein the disease or disorder is allograft rejection.  
   
   
       62 . The method of  claim 27 , wherein the disease or disorder is graft-versus-host disease.  
   
   
       63 . The method of  claim 27 , wherein the disease or disorder is multiple sclerosis.  
   
   
       64 . The method of  claim 27 , wherein the disease or disorder is Crohn's disease.  
   
   
       65 . The method of  claim 27 , wherein the disease or disorder is acute ulcerative colitis.  
   
   
       66 . The method of  claim 27 , wherein the disease or disorder is chronic ulcerative colitis.  
   
   
       67 . The method of  claim 27 , wherein the disease or disorder is a nosicomial infection.  
   
   
       68 . The method of  claim 27 , wherein the disease or disorder is Alzheimer's disease.  
   
   
       69 . The method of  claim 27 , wherein the disease or disorder is coeliac disease.