DEVICES AND METHODS FOR INHIBITING GRANULOCYTE ACTIVATION BY NEURAL STIMULATION

• US 20090062874A1
• Filed: 08/26/2008
• Published: 03/05/2009
• Est. Priority Date: 08/27/2007
• Status: Active Grant

• Current Assignee: The Feinstein Institutes For Medical Research
• Original Assignee: The Feinstein Institute for Medical Research (Northwell Health, Inc.)
• Inventors: Warren, Howland Shaw, Tracey, Kevin J., Metz, Christine N.
• Granted Patent: US 8,391,970 B2
• Time in Patent Office: Days
• US Class Current: 607/2
• CPC Class Codes: A61H 39/002 Using electric currents electrotherapy A61N1/32
• CPC Class Codes: A61H 39/007 Stimulation by mechanical vibrations, e.g. ultrasonic
• CPC Class Codes: A61N 1/36053 adapted for vagal stimulation A61N1/36114 takes precedence
• CPC Class Codes: A61N 1/36114 Cardiac control, e.g. by vagal stimulation stimulating the heart A61N1/362

Abstract

Described herein are methods, devices and systems for inhibition of granulocyte activation by appropriate stimulation of the vagus nerve. Methods of treating granulocyte-mediated disorders (including inflammatory disorders) by stimulating the vagus nerve to inhibit granulocyte activation (particularly neutrophil activation) are also described. Appropriate stimulation may be very low levels of stimulation, including stimulation that does not result in desensitization. The level of granulocyte activation may be detected and used to at least partially control stimulation.

Claims

1. A method of treating and/or preventing a granulocyte-mediated disease or disorder, the method comprising:

identifying a subject suffering from, or at risk for, a disease or disorder mediated by granulocyte activation; and

stimulating the subject'"'"'s inflammatory reflex in an amount sufficient to achieve an inhibition in expression of a marker of granulocyte activation without desensitizing the response of the granulocytes to vagal stimulation.

2. The method of claim 1, further comprising stimulating the subject'"'"'s inflammatory reflex to achieve a sustained reduction of expression of a marker of granulocyte activation.

3. The method of claim 1, further comprising stimulating the subject'"'"'s inflammatory reflex to achieve a reduction of expression of a marker of granulocyte activation without substantially reducing the expression of CD16b.

4. The method of claim 1, further comprising detecting expression of a marker of granulocyte activation.

5. The method of claim 4, wherein the marker of granulocyte activation is CD11b expression.

6. The method of claim 1, wherein the granulocytes affected by stimulation of the inflammatory reflex are neutrophils.

7. The method of claim 1, wherein the disease or disorder mediated by granulocyte activation is selected from the group consisting of:

diabetes, atherosclerosis, many cancers, septic shock, acute respiratory distress syndrome (ARDS), bacterial meningitis, acute pancreatitis, multiple organ failure (MOF), post-ischemic reperfusion, acute cellulitis, abdominal aortic aneurysm, asthma, osteomyelitis, Crohn'"'"'s disease, cystic fibrosis, emphysema, septic or bacterial pyelonephritis, rheumatoid arthritis, septic arthritis, uveitis, periodontitis, psoriasis, severe burns, skin ulceration, acute lung injury, pneumonia, trauma, severe early graft dysfunction, brochioeactasis, chronic obstructive pulmonary disease (COPD), complications with hemodialysis, hypersensitivity pneumonitis, lung fibrosis, herpes stromal keratitis, vascular restenosis, glomerulonephritis, hypersensitivity, cardiac rupture arising as a complication of myocardial infarction, multiple sclerosis, stroke and cerebral ischemia, and traumatic brain injury.

8. The method of claim 1, wherein the inflammatory reflex is stimulated by electrical stimulation.

9. The method of claim 1, wherein the inflammatory reflex is stimulated by mechanical stimulation.

10. The method of claim 1, wherein the inflammatory reflex is stimulated by electromagnetic stimulation.

11. The method of claim 1, wherein the stimulation comprises extremely low frequency, low level stimulation.

12. The method of claim 1, further comprising implanting a stimulator for stimulating the inflammatory reflex.

13. The method of claim 1, further comprising determining if the candidate is a candidate for inhibition of granulocyte activation by stimulation of the inflammatory reflex.

14. The method of claim 1, wherein the step of stimulating the inflammatory reflex comprises stimulating the vagus nerve.

15. A method of treating and/or preventing a granulocyte-mediated disease or disorder in a subject, the method comprising:

stimulating the subject'"'"'s vagus nerve in an amount sufficient to inhibit the expression of CD11b on the surface of the subject'"'"'s granulocyte cells without desensitizing the response of the granulocytes to vagal stimulation.

16. The method of claim 15, wherein the stimulation of the subject'"'"'s vagus nerve is sufficient to inhibit CD11b expression for a period of greater than 12 hours.

17. The method of claim 15, wherein the disease or disorder is selected from the group consisting of:

diabetes, atherosclerosis, many cancers, septic shock, acute respiratory distress syndrome (ARDS), bacterial meningitis, acute pancreatitis, multiple organ failure (MOF), post-ischemic reperfusion, acute cellulitis, abdominal aortic aneurysm, asthma, osteomyelitis, Crohn'"'"'s disease, cystic fibrosis, emphysema, septic or bacterial pyelonephritis, rheumatoid arthritis, septic arthritis, uveitis, periodontitis, psoriasis, severe burns, skin ulceration, acute lung injury, pneumonia, trauma, severe early graft dysfunction, brochioeactasis, chronic obstructive pulmonary disease (COPD), complications with hemodialysis, hypersensitivity pneumonitis, lung fibrosis, herpes stromal keratitis, vascular restenosis, glomerulonephritis, hypersensitivity, cardiac rupture arising as a complication of myocardial infarction, multiple sclerosis, stroke and cerebral ischemia, and traumatic brain injury.

18. The method of claim 15, wherein the stimulation is mechanical stimulation, electrical stimulation, or electromagnetic stimulation.

19. The method of claim 15, wherein the stimulation comprises pressure applied to the vagus nerve.

20. The method of claim 15, wherein the stimulation comprises extremely low frequency, low level stimulation.

21. The method of claim 15, further comprising implanting a stimulator configured to apply stimulation to the subject'"'"'s vagus nerve.

22. A method of treating and/or preventing a granulocyte-mediated disease or disorder in a subject, the method comprising:

detecting a granulocyte activation level; and

applying stimulation to the subject'"'"'s inflammatory reflex to inhibit granulocyte activation in response to the detected granulocyte activation level.

23. The method of claim 22, wherein the step of applying stimulation to the subject'"'"'s inflammatory reflex comprises stimulating the subject'"'"'s vagus nerve.

24. The method of claim 22, further comprising:

detecting a second granulocyte activation level; and

applying a second stimulation to the subject'"'"'s inflammatory reflex in response to the second subject'"'"'s vagus level.

25. The method of claim 22, wherein the step of detecting a granulocyte activation level comprises detecting expression of CD11b expression on granulocytes.

26. The method of claim 22, wherein the stimulation comprises mechanical stimulation.

27. The method of claim 22, wherein the stimulation comprises electrical stimulation.

28. The method of claim 22, wherein the stimulation comprises electromagnetic stimulation.

29. A system for treating and/or preventing a granulocyte-mediated disease or disorder in a subject, the system comprising:

a sensor to detect granulocyte activation level; and

a stimulator for stimulating a portion of the inflammatory reflex in response to the detected granulocyte activation level.

30. The system of claim 29, wherein the sensor configured to determine CD11b expression on granulocyte cells.

31. The system of claim 29, wherein the stimulator is configured to stimulate the subject'"'"'s vagus nerve in an amount sufficient to inhibit granulocyte activation without desensitizing the response of the granulocytes to vagal stimulation.

32. A system for treating and/or preventing a granulocyte-mediated disease or disorder in a subject, the system comprising:

a sensor to detect CD11b expression on neutrophils; and

a stimulator for mechanically stimulating a vagus nerve in response to the level of CD11b expression, whereby the neutrophil activation is inhibited.