mosby items and derived items © 2008, 2002 by mosby, inc., an affiliate of elsevier inc. chapter 9...

Mosby items and derived items © 2008, 2002 by Mosby, Inc., an affiliate of Elsevier Inc.

Chapter 9Chapter 9

Mucus-controlling Drug TherapyMucus-controlling Drug Therapy


Drug Control of Mucus: Drug Control of Mucus: A PerspectiveA Perspective

Mucociliary escalator is a major defense Mucociliary escalator is a major defense systemsystem

Failure may result in mechanical obstruction Failure may result in mechanical obstruction of the airwayof the airway

Properties of mucusProperties of mucus ProtectiveProtective Lubricative Lubricative Waterproofing Waterproofing Entraps microorganismsEntraps microorganisms


Clinical Indication for UseClinical Indication for Use

To reduce accumulation of airway secretions, To reduce accumulation of airway secretions, improve pulmonary function/gas exchange, reduce improve pulmonary function/gas exchange, reduce infection/damageinfection/damage

Diseases:Diseases: Cystic fibrosis (CF)Cystic fibrosis (CF) Chronic bronchitisChronic bronchitis PneumoniaPneumonia Diffuse panbronchiolitis (DPB)Diffuse panbronchiolitis (DPB) Primary ciliary dyskinesiaPrimary ciliary dyskinesia AsthmaAsthma BronchiectasisBronchiectasis


Clinical Indication for Use (cont’d)Clinical Indication for Use (cont’d)

Consider after:Consider after: Therapy to decrease infection/inflammationTherapy to decrease infection/inflammation Removal of irritants (including tobacco smoke)Removal of irritants (including tobacco smoke)


Physiology of the Mucociliary SystemPhysiology of the Mucociliary System

Source of airway secretionsSource of airway secretions Gel layerGel layer Periciliary layerPericiliary layer Surface epithelial cellsSurface epithelial cells

• Pseudostratified, columnar, ciliated epithelial cellsPseudostratified, columnar, ciliated epithelial cells

• Surface goblet cellsSurface goblet cells

• Clara cellsClara cells

Submucosal glandsSubmucosal glands• With serous and mucous cellsWith serous and mucous cells


Physiology of the Mucociliary System Physiology of the Mucociliary System (cont’d)(cont’d)

Terminology Terminology Mucoactive medicationsMucoactive medications ““Mucolytic”Mucolytic”

• Most medications mobilize secretions via method Most medications mobilize secretions via method other other thanthan direct thinning of mucus direct thinning of mucus



Surface epithelial cellsSurface epithelial cells 6000 goblet cells/mm6000 goblet cells/mm22 of normal airway of normal airway No No directdirect innervation of goblet cells innervation of goblet cells

Submucosal glandsSubmucosal glands Provide airway surface mucinProvide airway surface mucin Under parasympathetic controlUnder parasympathetic control



Ciliary systemCiliary system 200 cilia per cell200 cilia per cell Effective (power) strokeEffective (power) stroke Recovery strokeRecovery stroke Functional surfactant layer separates periciliary Functional surfactant layer separates periciliary

fluid from mucus gelfluid from mucus gel



Factors affecting mucociliary transportFactors affecting mucociliary transport Chronic obstructive pulmonary disease (COPD) Chronic obstructive pulmonary disease (COPD) Airway drying (such as with the use of dry gas for Airway drying (such as with the use of dry gas for

mechanical ventilation)mechanical ventilation) NarcoticsNarcotics Endotracheal suctioningEndotracheal suctioning



More factors affecting mucociliary transport More factors affecting mucociliary transport Airway traumaAirway trauma TracheostomyTracheostomy Cigarette smokeCigarette smoke Atmospheric pollutants (SOAtmospheric pollutants (SO22, NO, NO22, ozone) may transiently , ozone) may transiently

increase transport, especially at low concentration. At increase transport, especially at low concentration. At higher, toxic concentrations or with prolonged exposure higher, toxic concentrations or with prolonged exposure these decrease transport ratesthese decrease transport rates

Hyperoxia and hypoxiaHyperoxia and hypoxia



Food intake and mucus productionFood intake and mucus production No reported No reported association between milk and dairy association between milk and dairy

product intake and upper or lower respiratory tract product intake and upper or lower respiratory tract symptoms of congestion or nasal secretion weightsymptoms of congestion or nasal secretion weight


Nature of Mucus SecretionNature of Mucus Secretion

Healthy person secretes 100 ml/dayHealthy person secretes 100 ml/day Clear, viscoelastic, stickyClear, viscoelastic, sticky All but 10 ml reabsorbed in lungAll but 10 ml reabsorbed in lung

Structure and composition of mucusStructure and composition of mucus Two major classes of mucinsTwo major classes of mucins

• Secreted mucinsSecreted mucins

• Membrane-tethered mucinsMembrane-tethered mucins


Epithelial Ion TransportEpithelial Ion Transport

Under normal conditions:Under normal conditions: Healthy airway epithelia can absorb salt and water Healthy airway epithelia can absorb salt and water

driven by an active sodium transportdriven by an active sodium transport Normal epithelia can also secrete liquid into the Normal epithelia can also secrete liquid into the

periciliary fluid driven by an active chloride periciliary fluid driven by an active chloride transport through ion channels and passively transport through ion channels and passively through aquaporins or water channelsthrough aquaporins or water channels


Mucus in Disease StatesMucus in Disease States

Chronic bronchitisChronic bronchitis AsthmaAsthma BronchorrheaBronchorrhea Plastic bronchitisPlastic bronchitis Cystic fibrosisCystic fibrosis


Physical Properties of MucusPhysical Properties of Mucus

Adhesive forcesAdhesive forces Attractive forces between mucus and the airway Attractive forces between mucus and the airway

surfacesurface


Physical Properties of Mucus (cont’d)Physical Properties of Mucus (cont’d)

Cohesive forcesCohesive forces Attractive forces between like moleculesAttractive forces between like molecules SpinnabilitySpinnability RheologyRheology

• Study of the deformation and flow of matterStudy of the deformation and flow of matter ViscosityViscosity

• Resistance of a fluid to flowResistance of a fluid to flow Elasticity Elasticity

• Ability of a deformed material to return to its original Ability of a deformed material to return to its original shapeshape


Physical Properties of Mucus (cont’d) Physical Properties of Mucus (cont’d)

Mucus as a viscoelastic materialMucus as a viscoelastic material As a solid, a gel has elastic deformation, storing As a solid, a gel has elastic deformation, storing

energy with applied force energy with applied force As a liquid, a gel flows under applied force, losing As a liquid, a gel flows under applied force, losing

(dissipating) energy (dissipating) energy



Spinnability (cohesivity) of mucusSpinnability (cohesivity) of mucus Ability of mucus to be drawn out into threads was Ability of mucus to be drawn out into threads was

initially identified for cervical mucus and termed initially identified for cervical mucus and termed “spinability” “spinability”



Non-Newtonian nature of mucusNon-Newtonian nature of mucus In an ideal Newtonian liquid, the applied force to In an ideal Newtonian liquid, the applied force to

rate of flow remains constant with changing forcerate of flow remains constant with changing force A non-Newtonian substance, such as mucus, has A non-Newtonian substance, such as mucus, has

changing viscosity (defined as the proportionality changing viscosity (defined as the proportionality constant of force to flow) with varying applied force constant of force to flow) with varying applied force (shear rate)(shear rate)


Mucoactive AgentsMucoactive Agents

Mucolysis and mucociliary clearanceMucolysis and mucociliary clearance Mucolytic agents decrease the elasticity and Mucolytic agents decrease the elasticity and

viscosity of mucus because the gel structure is viscosity of mucus because the gel structure is broken downbroken down

Therapeutic options for controlling hypersecretionTherapeutic options for controlling hypersecretion• Remove causative factorsRemove causative factors

• Optimize tracheobronchial clearanceOptimize tracheobronchial clearance

• Use mucoactive agents when indicatedUse mucoactive agents when indicated


Mucoactive Agents (cont’d)Mucoactive Agents (cont’d)

Mucolytics and expectorantsMucolytics and expectorants Classic mucolytics reduce mucins by severing Classic mucolytics reduce mucins by severing

disulfide bonds or charge shieldingdisulfide bonds or charge shielding


NN-Acetyl-L-cysteine (NAC)-Acetyl-L-cysteine (NAC)

Indications for useIndications for use Treatment of conditions associated with viscous Treatment of conditions associated with viscous

secretions secretions • Despite in vitro mucolytic activity and a long history of Despite in vitro mucolytic activity and a long history of

use, no data demonstrate oral or aerosolized NAC is use, no data demonstrate oral or aerosolized NAC is effective for any lung disease.effective for any lung disease.

Acetaminophen overdoseAcetaminophen overdose


NN-Acetyl-L-cysteine (cont’d)-Acetyl-L-cysteine (cont’d)

Mode of actionMode of action NAC disrupts the structure of the mucus polymer NAC disrupts the structure of the mucus polymer

by substituting free thiol (sulfhydryl) groups for the by substituting free thiol (sulfhydryl) groups for the disulfide bonds connecting mucin proteinsdisulfide bonds connecting mucin proteins



HazardsHazards BronchospasmBronchospasm

• Less common with 10% solutionLess common with 10% solution

Mechanical obstruction of airwayMechanical obstruction of airway



Incompatibility with antibiotics in mixtureIncompatibility with antibiotics in mixture Sodium ampicillinSodium ampicillin Amphotericin BAmphotericin B Erythromycin lactobionateErythromycin lactobionate Tetracyclines (tetracycline, oxytetracycline)Tetracyclines (tetracycline, oxytetracycline) AminoglycosidesAminoglycosides


Dornase Alfa (Pulmozyme)Dornase Alfa (Pulmozyme)

Indications and use in CFIndications and use in CF Dornase alfa is indicated for the management of Dornase alfa is indicated for the management of

CF, to reduce the frequency of respiratory CF, to reduce the frequency of respiratory infections requiring parenteral antibiotics, and to infections requiring parenteral antibiotics, and to improve or preserve pulmonary function in these improve or preserve pulmonary function in these subjectssubjects


Dornase Alfa (Pulmozyme) (cont’d)Dornase Alfa (Pulmozyme) (cont’d)

Mode of actionMode of action Reduces viscosity and adhesivity by breaking Reduces viscosity and adhesivity by breaking

down DNAdown DNA Dose and administrationDose and administration

Available as single-use ampoule Available as single-use ampoule • 2.5 mg of drug in 2.5 ml 2.5 mg of drug in 2.5 ml

Should be refrigerated and protected from lightShould be refrigerated and protected from light



Dose and administrationDose and administration Available as single-use ampoule Available as single-use ampoule

• 2.5 mg of drug in 2.5 ml 2.5 mg of drug in 2.5 ml Should be refrigerated and protected from lightShould be refrigerated and protected from light

Dose and administration (cont’d)Dose and administration (cont’d) Usual dose is 2.5 mg daily Usual dose is 2.5 mg daily Delivered by one of the following tested and Delivered by one of the following tested and

approved nebulizers: approved nebulizers: • Hudson RCI UP-DRAFT II OPTI-NEB Hudson RCI UP-DRAFT II OPTI-NEB • Acorn II nebulizer Acorn II nebulizer • PARI LC PLUS nebulizerPARI LC PLUS nebulizer



Adverse effectsAdverse effects Little difference between dornase alfa (3%) and Little difference between dornase alfa (3%) and

placebo (2%)placebo (2%) Common side effects: Common side effects:

• Voice alteration Voice alteration • Pharyngitis Pharyngitis • Laryngitis Laryngitis • RashRash• Chest pain Chest pain • ConjunctivitisConjunctivitis



Clinical application and evaluationClinical application and evaluation Based not only on lung function Based not only on lung function Also based on a reduction in the number and Also based on a reduction in the number and

severity of infectious exacerbations severity of infectious exacerbations Thus the need for antibiotics and hospitalization Thus the need for antibiotics and hospitalization


F-Actin-depolymerizing Drugs: F-Actin-depolymerizing Drugs: Gelsolin and Thymosin Gelsolin and Thymosin 44

Gelsolin, an 85-kD actin-severing peptide, has been Gelsolin, an 85-kD actin-severing peptide, has been shown to reduce the viscosity of CF sputum in a shown to reduce the viscosity of CF sputum in a dose-dependent mannerdose-dependent manner

Thymosin Thymosin 44 decreases sputum cohesivity in a dose- decreases sputum cohesivity in a dose-dependent and time-dependent mannerdependent and time-dependent manner

In vitroIn vitro studies have shown that F-actin- studies have shown that F-actin-depolymerizing agents along with dornase alfa result depolymerizing agents along with dornase alfa result in greater reduction in sputum cohesivity and in greater reduction in sputum cohesivity and viscoelasticity than either agent aloneviscoelasticity than either agent alone


ExpectorantsExpectorants

Iodide-containing agentsIodide-containing agents Iodide-containing agents (e.g., SSKI or super- Iodide-containing agents (e.g., SSKI or super-

saturated potassium iodide) are generally saturated potassium iodide) are generally considered to be considered to be expectorantsexpectorants

Thought to stimulate the secretion of airway fluid Thought to stimulate the secretion of airway fluid


Expectorants (cont’d)Expectorants (cont’d)

Sodium bicarbonateSodium bicarbonate By increasing the local bronchial pH, sodium By increasing the local bronchial pH, sodium

bicarbonate weakens the bonds between the side bicarbonate weakens the bonds between the side chains of the mucus molecule, resulting in chains of the mucus molecule, resulting in lowering of the mucus viscosity and elasticitylowering of the mucus viscosity and elasticity

Has not been clinically demonstrated to improved Has not been clinically demonstrated to improved airway mucus clearanceairway mucus clearance



GuaifenesinGuaifenesin Generally considered an Generally considered an expectorantexpectorant

• May stimulate the cholinergic pathway and induce May stimulate the cholinergic pathway and induce increased mucus secretion from the airway submucosal increased mucus secretion from the airway submucosal glands glands

• Has not been demonstrated to be clinically effective in Has not been demonstrated to be clinically effective in randomized controlled trialsrandomized controlled trials



Dissociating solventsDissociating solvents Urea is a dissociating agent that can break ionic Urea is a dissociating agent that can break ionic

and hydrogen bondsand hydrogen bonds• Disrupts the hydrogen bonds between the Disrupts the hydrogen bonds between the

oligosaccharide side chains of the neighboring mucus oligosaccharide side chains of the neighboring mucus molecules molecules

• May also decrease the interaction between DNA May also decrease the interaction between DNA moleculesmolecules

• Mucolytic action of urea occurs only at very high Mucolytic action of urea occurs only at very high concentrations of urea (3-8 mol/L) concentrations of urea (3-8 mol/L)

Not appropriate for human useNot appropriate for human use



OligosaccharidesOligosaccharides Oligosaccharide side chains make up about 80% Oligosaccharide side chains make up about 80%

of mucin structureof mucin structure Bonds are weak and can be disrupted by agents Bonds are weak and can be disrupted by agents

such as such as • DextranDextran

• Mannitol Mannitol

• Lactose Lactose



P2YP2Y22 Agonists Agonists Chloride conductance through the CaChloride conductance through the Ca2+2+-dependent chloride -dependent chloride

channels is preserved in the CF airwaychannels is preserved in the CF airway The tricyclic nucleotides UTP and ATP regulate ion transport The tricyclic nucleotides UTP and ATP regulate ion transport

through P2Ythrough P2Y22 purinergic receptors purinergic receptors UTP aerosol increases transepithelial potential difference UTP aerosol increases transepithelial potential difference

• There is active development of novel P2YThere is active development of novel P2Y22 purinergic receptor purinergic receptor agonists for clinical use agonists for clinical use


Mucokinetic AgentsMucokinetic Agents

Increase cough clearance by increasing Increase cough clearance by increasing expiratory airflow or by reducing sputum expiratory airflow or by reducing sputum adhesivity and tenacityadhesivity and tenacity

BronchodilatorsBronchodilators Increase ciliary beat, but this has little effectIncrease ciliary beat, but this has little effect May increase mucus productionMay increase mucus production


Surface-active PhospholipidsSurface-active Phospholipids

Thin surfactant layer between the periciliary fluid and Thin surfactant layer between the periciliary fluid and the mucous gel the mucous gel Prevents airway dehydrationPrevents airway dehydration Permits mucus spreading on extrusion from glands Permits mucus spreading on extrusion from glands Allows efficient ciliary coupling with mucusAllows efficient ciliary coupling with mucus More importantly, allows ciliary release from mucus once More importantly, allows ciliary release from mucus once

kinetic energy is transmittedkinetic energy is transmitted Surfactant therapy has been shown effective in Surfactant therapy has been shown effective in

treating chronic bronchitis and CFtreating chronic bronchitis and CF


Mucoregulatory MedicationsMucoregulatory Medications

Decrease mucus hypersecretionDecrease mucus hypersecretion SteroidsSteroids Indomethacin (Japan)Indomethacin (Japan) AnticholinergicsAnticholinergics

• AtropineAtropine

• Ipratropium bromideIpratropium bromide

• Tiotropium Tiotropium

Macrolide antibioticsMacrolide antibiotics


Other Mucoactive AgentsOther Mucoactive Agents

AntiproteasesAntiproteases It has been shown that neutrophil proteases cause It has been shown that neutrophil proteases cause

a secretory response from submucosal glands a secretory response from submucosal glands with an increase in mucus production with an increase in mucus production

αα11-Antitrypsin-Antitrypsin Recombinant secretory leukocyte protease Recombinant secretory leukocyte protease

inhibitor (rsLPI)inhibitor (rsLPI)


Other Mucoactive Agents (cont’d)Other Mucoactive Agents (cont’d)

Hyperosmolar salineHyperosmolar saline MayMay increase FEV increase FEV11 in patients in patients

Alternate effect is Alternate effect is decreaseddecreased FEV FEV11

Unpleasant taste; coughing may make it Unpleasant taste; coughing may make it unsuitable for long-term useunsuitable for long-term use


Gene TherapyGene Therapy

Centered on complementary DNA transfer of the Centered on complementary DNA transfer of the normal CFTR gene in CF patients normal CFTR gene in CF patients

For gene transfer to be effective, the vector and its For gene transfer to be effective, the vector and its package must be package must be NonimmunogenicNonimmunogenic Stable to shear forces during aerosolization Stable to shear forces during aerosolization Safe for transfected cellsSafe for transfected cells

Viral vectors that have been studied include Viral vectors that have been studied include AdenovirusesAdenoviruses Adeno-associated virusAdeno-associated virus LentivirusLentivirus


Using Mucoactive Therapy With Using Mucoactive Therapy With Physiotherapy and Airway Clearance Physiotherapy and Airway Clearance

DevicesDevices GravityGravity

Not a primary mechanism for normal mucociliary Not a primary mechanism for normal mucociliary transporttransport

Postural drainage may show benefit Postural drainage may show benefit when when incorporated into conventional chest incorporated into conventional chest physiotherapy (CPT)physiotherapy (CPT)


Using Mucoactive Therapy with Using Mucoactive Therapy with Physiotherapy and Airway Clearance Physiotherapy and Airway Clearance

Devices (cont’d)Devices (cont’d) Insufflation-ExsufflationInsufflation-Exsufflation

Inflates the lungs with positive pressure followed Inflates the lungs with positive pressure followed by a negative pressure to simulate a coughby a negative pressure to simulate a cough

Cycle begins with inspiratory pressure 25 to 35 Cycle begins with inspiratory pressure 25 to 35 cmHcmH22O for 1 to 2 seconds, followed by an O for 1 to 2 seconds, followed by an expiratory pressure of 30 to 40 cmHexpiratory pressure of 30 to 40 cmH22O for 1 to 2 O for 1 to 2 secondsseconds

Can be used with an oronasal mask or attached to Can be used with an oronasal mask or attached to an artificial airway an artificial airway



Devices (cont’d)Devices (cont’d) Active cycle of breathing and forced Active cycle of breathing and forced

expiratory technique (FET) maneuverexpiratory technique (FET) maneuver Combination of Combination of

• Breathing control (relaxed diaphragmatic breathing)Breathing control (relaxed diaphragmatic breathing)

• Thoracic expansion control (deep breaths)Thoracic expansion control (deep breaths)

• Forced expiration technique from progressively Forced expiration technique from progressively increasing lung volumesincreasing lung volumes

No documented studies showing benefit No documented studies showing benefit



Devices (cont’d)Devices (cont’d) Autogenic drainageAutogenic drainage

Aims to "optimize" airflow in the various Aims to "optimize" airflow in the various generations of bronchi to move secretionsgenerations of bronchi to move secretions

Has Has notnot been demonstrated to be as effective as been demonstrated to be as effective as CPT in mobilizing secretionsCPT in mobilizing secretions



Devices (cont’d)Devices (cont’d) Incorporates staged breathing starting with small tidal Incorporates staged breathing starting with small tidal

breaths from expiratory reserve volume (ERV), breaths from expiratory reserve volume (ERV), repeated until secretions "collect" in the central repeated until secretions "collect" in the central airways airways

Patients are instructed to suppress cough, and a Patients are instructed to suppress cough, and a larger volume is taken for a series of 10-20 breaths, larger volume is taken for a series of 10-20 breaths, followed by a series of even larger (approaching vital followed by a series of even larger (approaching vital capacity [VC]) breaths, and followed by several huff capacity [VC]) breaths, and followed by several huff coughscoughs



Devices (cont’d)Devices (cont’d) ExerciseExercise

Causes increased sputum production compared Causes increased sputum production compared with rest with rest

Appears to augment bronchial hygiene Appears to augment bronchial hygiene Should not substitute for other bronchial hygiene Should not substitute for other bronchial hygiene

regimensregimens



Devices (cont’d)Devices (cont’d) Positive airway pressure techniquesPositive airway pressure techniques

Can be effective alternatives to chest physical Can be effective alternatives to chest physical therapy in expanding the lungs and mobilizing therapy in expanding the lungs and mobilizing secretionssecretions• CoughCough

• FETFET

• Pursed-lipped breathing Pursed-lipped breathing



Devices (cont’d)Devices (cont’d) High-frequency techniquesHigh-frequency techniques

High-frequency oscillation (HFO) of the air column High-frequency oscillation (HFO) of the air column in the conducting airways has been shown to in the conducting airways has been shown to enhance clearance of secretions enhance clearance of secretions



Devices (cont’d)Devices (cont’d) Oscillation of the airwayOscillation of the airway

The FLUTTERThe FLUTTER The PercussionatorThe Percussionator



Devices (cont’d)Devices (cont’d) Chest wall oscillationChest wall oscillation

The VestThe Vest Has been reported to be effective for secretion Has been reported to be effective for secretion

clearance in patients with CF clearance in patients with CF Conjecture is that this device has a role in lung Conjecture is that this device has a role in lung

expansion for patients other than those with cystic expansion for patients other than those with cystic fibrosis in the acute care settingfibrosis in the acute care setting


Future Mucus-controlling AgentsFuture Mucus-controlling Agents

Thicker and denser strands of mucus would be Thicker and denser strands of mucus would be moved more efficiently by ciliary contact and elastic moved more efficiently by ciliary contact and elastic recovery than would thin, low-viscosity solutions recovery than would thin, low-viscosity solutions

Endotracheal aspiration of secretions using suction Endotracheal aspiration of secretions using suction would be easier with low-viscosity mucuswould be easier with low-viscosity mucus

Treatment of bronchial hypersecretion would be Treatment of bronchial hypersecretion would be better aimed at better aimed at normalizingnormalizing the rheological properties the rheological properties of mucus to optimize transport of mucus to optimize transport Musospissic agentsMusospissic agents


Respiratory Care Assessment of Respiratory Care Assessment of Mucoactive Drug TherapyMucoactive Drug Therapy

Before treatmentBefore treatment Level of consciousness (LOC)Level of consciousness (LOC) Adequacy of coughAdequacy of cough Need for bronchial hygieneNeed for bronchial hygiene


Respiratory Care Assessment of Respiratory Care Assessment of Mucoactive Drug Therapy (cont’d)Mucoactive Drug Therapy (cont’d)

During treatment and short termDuring treatment and short term Correct use of equipmentCorrect use of equipment Airflow changesAirflow changes Mucus productionMucus production Respiratory rate and patternRespiratory rate and pattern Subjective responseSubjective response Adverse reactionsAdverse reactions



Long termLong term Number and severity of:Number and severity of:

• InfectionsInfections

• ER visitsER visits

• HospitalizationsHospitalizations

Need for antibioticsNeed for antibiotics Pulmonary function testingPulmonary function testing



General contraindicationsGeneral contraindications Profound airflow compromiseProfound airflow compromise

• FEVFEV11 < 25% predicted < 25% predicted

Severely compromised:Severely compromised:• VCVC

• Expiratory flowExpiratory flow

Gastroesophageal reflux disease (GERD)Gastroesophageal reflux disease (GERD) Inability to protect airwayInability to protect airway Acute bronchitis or exacerbation of chronic Acute bronchitis or exacerbation of chronic

disease may leave patient less responsive to disease may leave patient less responsive to treatmenttreatment

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mucous cells

mucus gel slide

direct thinning of mucus

use contd

airway surface mucin