Stuart M. Brooks, MD University of South Florida

Size: px

Start display at page:

Download "Stuart M. Brooks, MD University of South Florida"

Abner Baker
6 years ago
Views:

1 Prof. JOHN GUY WIDDICOMBE /26/2011 Stuart M. Brooks, MD University of South Florida An eminent scholar in the evolving field of cough research Current Opinion in Pharmacology (2002); 2: Big Bang 13.7 BYA Origin of Earth 4.6 BYA Monocellular Life 3.8 BYA Multicellular Life 2.1 BYA Land Plant BYA Fish BYA Arthropod BYA Eukaryote 1.5 BYA Forest BYA Amphibian BYA Bee BYA Insect BYA Mammal BYA Reptile BYA Flower BYA Dinosaur BYA Bird BYA COUGH REFLEX IS LIKE CONDUCTING A SYMPHONY ABDOMINAL MUSCLES NOCICEPTORS PERIPHERAL NERVES Dinosaur BYA Lemur BYA Orangutan BYA Gorilla BYA Mammal BYA Lorises/Pottos BYA Bushbabies BYA Old world monkey BYA Chimpanzee/ Human BYA Placenta Mammal BYA Became Extinct BYA New world monkey BYA Tarsiers BYA Chronohomo species BYA Gibbon BYA Primate BYA Hominidae/Great Apes BYA Homo sapiens BYA 1

2 AEGYPTOPITHECUS 30 MYA Purgatorius 65 MYA Prehensile 5-digits Feet with flat nails Not claws Depth perception Forward-facing eyes Primates Appear 85 MYA Dryomomys 55 MYA Environment Climate Food Availability Water Accessibility Competitors Genetics Mass Extinctions Life Evolution Evolved Species Hominine History & Cough Chimpanzee CHEMOSENSORY 200 TYA Brain large Australopithecines Homo ergaster Homo erectus Homo-Chimp Common Ancestor Extinct Neanderthal 700 TYA 1.6 MYA Descent of Larynx MECHANOSENSORY 7 MYA Homo Species Evolution 4 MYA Bipedalism Australopithecines 2.5 MYA Brain Enlarges Australopithecines Homo habilis Animals with Cough Reflex 1. Cat 2. Dog 3. Monkeys 4. Rabbit 5. Ferret 6. Cow 7. Guinea pig 8. Humans Evolution of Homo species 6 MYA Ardipithecus Australopithecus Present Homo sapiens Stimuli Provoking Cough in Animal & Humans MECHANICAL STIMULATION Mucus (Canning B. Lung. 2008; 186 (Suppl 1): S23 S28) Foreign Body Tumor TRPV1 Receptor Activation Capsaicin Acid Autacoids and 2 nd messengers (e.g. HETEs, bradykinin, adenosine) BRADYKININ Asthma Viral infections ACE Inhibitor CITRIC ACID AND TARTARIC ACID Aspiration Airway acidification in disease (as measured by exhaled breath condensate) LOW CHLORIDE AND/ OR NON-ISOSMOTIC AEROSOLS Aspiration Fog 2

3 Monotremes Split MYA (lay eggs) Eutheria (placental mammals) Loss of Smell Development of Speech Food Availability Water Accessibility Competitors Genetics Mass Extinctions 110 MYA Life Evolution Cough Cough Becomes Different in Humans 110 MYA Ability to Cough Refiguring & neuroplastic transformation of normal breathing utilizing same muscles & nerves to evolve reflex cough Human Evolution 5-6 MY Cough Evolution Brain Growth Speech Living Together Co-evolution (virus) MECHANOSENSORY COUGH Provoked by mechanical touch and acid Evolved when hominids first created phonation and speech Protective mechanism against aspirated gastric content Larynx moved closer to opening of esophagus Anesthetized guinea pigs true cough receptor Why do Human s Cough? Protective But against what? 3-MODULATION Canning. Lung. 2008; 186 (Suppl 1): S23 S28 Cough Reflex Arc 1-TRANSDUCTION Diaphragm 3

4 Comparison of Chimpanzee and Human Evolution of Language Tongue Lengthening of Laryngopharynx Differences in Supralaryngeal Vocal Tract (SVT) SVT is divided into 2 cavities with a right-angle bend Disproportionate SVT Horizontal portion (mouth & oropharynx) Living Together Infectious Disease Irritant Exposures Growing Brain Competitors Genetics Mass Extinctions Vertical portion (palate to vocal cords) Proportionate SVT Life Evolution Cough Specialization of speech Living Together Brain Tongue, Lips, & Larynx control and coordination Jaw & Palatal muscles fatigue resistant Kent (2004) Proc. From Sound to Sense Vocalis muscle slow tonic fatigue resistant fibers Speech Risk for Irritants and Infectious Disease Due to Living in Close Quarters 4

5 Chemosensory cough 1. Cough becomes defensive warning like pain 2. Brain enlarges & gains more control 3. Living together, infections/irritants, ion channels 4. Neuroinflammation 1 st line innate immunity for lung infection? 5. Co-evolution of primitive viruses enhances viral spread and contagion? Fire & Cooking Fire & Cooking stimulated growth of human brain Not enough hours in day to gain enough energy to sustain a larger brain Takes 8.8 hours for gorillas 7.8 hours for orangutans 7.3 hours for chimps 9.3 hours for humans Human ancestors got energy to grow brains with 3 X neurons as gorillas, with invention of cooking Stimulus COUGH INFLAMMATION Irritant Chemicals C fiber NEUROGENIC INFLAMMATION BRAIN Urge to Cough Inhibit INFLUENCES OF HUMAN BRAIN ON COUGH NOCICEPTORS EVOKED COUGH Activate Capsaicin Citric Acid Autacoids, HETES, Bradykinin, Adenosine Bötzinger Ventral Respiratory Group Nociceptor Activate Glottis Diaphragm Abdominal Muscles Inhibitory General Anesthesia Sleep Voluntary Theory: Social competition is major Population density cause of increased cranial capacity Population density triggered rapid growth of human brain over past 2 million years Brain size increases most in areas with larger populations Coping with climate = less a factor than coping with other people Brain Wiring- SRGAP gene SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2) (i.e., Formin-binding protein 2, FNBP2) Emerged 2-3 MYA when Homo evolved from Australopithecus Bigger brains developed stone tools culture became more sophisticated Only humans have 3 extra copies of SRGAP gene SRGAP2C (duplicated 1 MYA) activated in developing brain of infant & controls growth and movements of nerve cells 5

6 FOXP2 Protein/Gene FOXP2 (Forkhead Box Protein P2)-gene implicated in speech and language Expression of brain FoxP1 and FoxP2 similar in humans & songbird Sensorimotor integration and control of skilled, coordinated movement Other primates and rodents cannot modify innate vocalizations Human FOXP2 differs from chimp FOXP2 by 2 amino acids, mouse FOXP2 by 3 amino acids, and zebra finch FOXP2 by 7 amino acids Pathways Activated During Capsaicin-induced Cough (Teramitsu et al., Journal of Neuroscience, 2004) ASPM = "Abnormal Spindlelike, Microcephaly-associated protein (gene) New version of ASPM appeared ~58 TYA Roughly correlates with development of written language, spread of agriculture and development of cities PATHWAYS ACTIVATED DURING URGE-TO-COUGH Premotor Inferior parietal lobule Superior temporal gyrus Orbitofrontal cortex Inferior frontal gyrus Middle frontal gyrus Anterior mid-cingulate cortex Insula Cerebellum Blood Oxygen Level-Dependent (BOLD) Responses During Coughing Functional Magnetic Resonance Imaging (fmri) Mazzone et al- J Neuroscience (2011);31(8): First Line of Defense Ion Channels Signifying Neural Activity 6

7 Ion Channels (Nociceptors) Ion channels evolved over millions of years Most life forms, from bacteria to higher plants and animals, contain ion channels Ion channels permit passage of charged ions across impermeable lipid bilayers cellular membranes Calcium Ion Influx for Nerve Propagation Intracellular Ca 2+ 20,000 lower <extracellular concentrations Afferent Sensory Nerve Ion Channel TRP protein functions as controls cell s Ca 2+ Miniscule electrical current (perhaps a few trillionth of an amp) permits an afferent sensory nerve cell to depolarize and propagate a nerve impulse TRP Channels Influence Biological Functions Photoreception Pheromone sensing Taste perception Thermo sensation Pain perception Mechanosensation Perceives pungent compounds mustard, garlic, menthol, camphor, hot pepper ) Renal Ca 2+ /Mg 2+ handling Smooth muscle tone Blood pressure regulation Mediators of inflammation Non-sensitized TRPV1 Chronic irritant exposure Neuropeptides Neurogenic Inflammation Sensitized Unregulated Increased receptor number Response to other stimuli H +, Heat Ca 2+ Na + Protein Kinase Activation Extracellular PKC INDIRECT SENSITIZATION Intracellular Capsaicin binding site S1 S2 S3 S4 S5 A DIRECT SENSITIZATION A A N C S6 PLC TRP domain Channel pore P-loop ph sensitivity Persistent Cough 7

8 Fear of Infectious Cough Droplet nuclei What was covered 1. What is the Cough Reflex? -Like Conducting a Symphony 2. Everyone Coughs 3. Evolutionary Time-Line & Human Chronospecies 4. Bipedalism, Use Of Tools, Brain Growth, Anatomic Changes 5. Gene mutations/ adaptations 6. Environmental events, genetic bottlenecks TRPV-1 expression vs. capsaicin PC 5 response (µm) A significant correlation between TRPV-1 expression and the PC 5 Capsaicin challenge response ) in 29 patients with chronic cough (Groneberg, AJRCCM, 2004) r = 0.41 P = What was covered 7. Climate Change & Catastrophic Events 8. Beginning of cough reflex and animals with cough 9. Mechanosensory, speech, descent of larynx & supra-laryngeal vocal tract 10. Chemosensory - living together, infections/irritants, ion channels & neurogenic inflammation Post-viral infection change in cough reflex cough reflex sensitivity Cough reflex sensitivity Innocuous stimulus Baseline Viral URTI Time post viral infection Persistent cough reflex sensitivity Baseline Noxious stimulus Day 0 Day 21? Months/ Years POST-VIRAL INFECTION COUGH REFLEX may remain activated leading to chronic cough provoked by exposures such as scents, aerosols and changes in air temperature Evolutionary Outcomes 1. Cough becomes defensive warning like pain 2. Mechanosensory cough, speech, descent of larynx & supra-laryngeal vocal tract 3. Chemosensory cough living together, infections/irritants, ion channels & neurogenic inflammation a. Neuroinflammation 1 st line innate immunity for lung infection? b. Co-evolution of primitive viruses enhances viral spread and contagion? 8

211MDS Pain theories

211MDS Pain theories Definition In 1986, the International Association for the Study of Pain (IASP) defined pain as a sensory and emotional experience associated with real or potential injuries, or described