Post on 08-Aug-2015
5th RMH FESS and 3rd Rhinoplasty CourseRiyadh Military Hospital
Sunday, Nov 13, 2011
Steven M. Houser, MD, FAAOAAssociate Professor,
Case Western Reserve UniversityCleveland Ohio, USA
Nasal Mucosal Defense and Mucociliary Clearance
Outline
• Adaptive• T and B cells
• Innate• Nasal/respiratory mucus• Cilia• Mucous membrane • Mucociliary Clearance (MCC)• Selected diseases affecting MCC
Adaptive Immunity
• CRS mediated by T helper cells• Th1
• INF-γ, TNF-α: activate macrophages and cytotoxic T lymphocytes
• Th2• IL-4,5,9,13: promote IgG & IgE production, support eosinophils
& mast cells
• IL-13 pro-eo role appears central to CRS
• Generally Th1 and Th2 effects counter/balance each other
Ramanathan, Oto HNS, 2007
Innate Immunity
• Respiratory epithelium critical for innate immunity• appropriate mucus/periciliary fluid• coordinated ciliary activity
• Respiratory secretions consist of:• 95% water• 1% sodium chloride• 0.5-1% free protein• 0.5-1% mucins (glycoproteins)
Houtmeyers, Eur Respir J 1999
Respiratory Mucus
• Gel and sol layers• 10 m thick• 1 to 2 L per day are
produced under normal circumstances
• Mucus noted when:• Too much produced• Too dry
Respiratory Mucus
• Gel:• Produced by goblet cells and submucosal glands• Mucin (glycoprotein)• Immunoglobulins (IgG/A), albumin, lactoferrin, lysozyme
• Sol:• Periciliary fluid• Nonciliated columnar cells (microvilli)• Minimal glycoprotein, serum protein
• H2O, electrolytes
Respiratory Mucus
• Mucus swept to nasopharynx by MCC at 1cm/min
• Mucus blanket swallowed & replaced q10-20min under resting conditions
• (MCC to follow later)
Respiratory Mucus
• Major proteins:• Albumin 15%• IgG 2-4%• s-IgA 15%• Lactoferrin 2-4%• Lysozyme 15-30%• Secretory leukoprotease inhibitor 10%• Mucous glycoproteins (MGP) 10-15%
Mucus glycoprotein (MGP)
• 2-400,000 daltons• Rapid turnover• Traps particulates, and removed per
MCC• Insulates mucosa below• Traps moisture below gel layer• Acts as a reservoir for humidification of
inspired/expired air• MUC1, MUC4, MUC16, MUC5AC,
MUC5B
Immunoglobulins
• Plasma cells in mucosa make 25% IgG, 75% IgA• S-IgA binds microorganisms
in airway
• IgG acts within the mucosa itself
• IgG appears more essential for defense IgG
Lysozyme
• 14,000 daltons (small)• Produced by serous cell of
submucosal glands• Kills airborne bacteria• Prevents mucosal infection
Lactoferrin
• Made by serous cells• Bacteriostatic and
bacteriocidal• Binds iron, this seems to
play a role in its action to kill bacteria
Additional innate defense molecules
• membrane-permeabilizing defensins
• cathelicidins
• secretory leukoprotease inhibitor (SLPI)
• elafin
• calcium-dependent collectins• pulmonary surfactant proteins (SPA and SP-D)• serum-derived mannose binding protein.
Kauffman, Clin Rev All Immunol 2006
Surfactant
• Phospholipids make up 80-90%
• Surfactant proteins 10-15%• surfactant proteins (SPA and SP-D)
• Antimicrobial properties v Staph, Pseudo, Strep• Inhibit growth of G(-) bacteria• Dampen allergic immune response
• Coats gel layer to reduce surface tension• Reduces mucosal viscosity at gel-sol interface• Aids in elimination of deposited particles
Schlosser, Ann Otol Rhinol Laryngol 2006
Toll-like receptors (TLR)
• Transmembrane pattern recognition proteins
• Embryologically ancient• Originally identified in Drosophila (fruit flies)
• Macrophages, dendritic cells, endothelial & epithelial cells
• Recognize molecular patterns• Endotoxin, flagellin, lipopeptides, ds RNA, bacterial DNA• Local immune response• Initiate communication with adaptive immune system
Ramanathan, Oto HNS, 2007
Cilia
• Axoneme• 2 central microtubules• 9 doublets with dynein arms
• 6 m long x 0.2 m diameter
• Tipped by a “crown with bristles”
• Glycocalyx sheath
• 200 per ciliated cell
• 109 cilia/cm2 in respiratory tract
Cilia
• Normal CBF: 12-15 Hz• Effective stroke:1 :: recovery stroke:3• Weight capacity: 20mg/mm2
• 50%+ epith. destroyed before effect• Transplant maintains previous direction• Metachronal rhythm
• adjacent cilia recruited per hydrodynamic forces and intracellular communication
Meeks, Pediatric Pulmonary 2000
GelSol
Cilia
• Tubular anomalies: secondary, assoc. with infection, of minor importance
• Compound cilia: irrelevant finding
Toskala, Acta Otolaryngol 1995
Mucous Membrane
• Pseudostratified ciliated columnar• 100-200 cm2 mucosal surface within nose
• Ciliated (near 80% cells)• Goblet (near 20% cells)• Non-ciliated• Basal• (Clefts with normal epithelium)Al-Rawi, Laryngoscope 1998
Cohen, Ann Oto Rhin Laryng 2006
microvillar gobletciliated
basal
Mucous Membrane
• Submucosa• tubuloalveolar
seromucinous glands• blood vessels• nerves• transient inflammatory
cells
Mucociliary Clearance
• Mucus + ciliated epith. work together
• 6 mm/min. (range 1 - 20)
• 10 - 20 min. to clear inhaled particles
• Nearly 100% particles >4 m removed
Sinuses
• Pseudostratified ciliated columnar
• Approx. 300 cm2 surface• 5% of mucus = from sinus
• scant submucosal glands
• less goblet cells (except maxillary)
Mucus Flow
• Floor directly posterior to soft palate
• Low/mid septum upward and straight back
• Upper septum downward to inf/post vomer
• Inf turb lateral undersurface to torus
• Ant inf turb (1 cm) anterior
Waguespack, Laryngoscope 1995
Mucus Flow
• Maxillary sinus: star-shaped from bottom of sinus to natural ostium
• Frontal: sweeps in a large curve rising from medial roof lateral nasofrontal duct
• Ethmoid and sphenoid not precisely described
Mucus Flow
• Ant ethmoidectomy with antrostomy• Tracer circles around antrostomy post/inf direction to
inf turb pharynx
• Ant/post ethmoidectomy with antrost.• Post eth ant eth post/inf to inf turb• Post ethmoid recirculation (clockwise)• Rare stasis at junction ant & post ethmoid
Mucus Flow
• Partially resected middle turbinate• Superior
• Up to uncinate ant/inf to inf turb• Directly posterior along lateral undersurface
• Inferior• Inferior along undersurface• Lateral• Medial
Mucus Flow
• Lateral wall concha bullosa taken• Tracer moved laterally ant eth region
• Sphenoid• Med and lat toward ostium
• Along rostrum to nasopharynx (NP)• Posterior ethmoid ant inf turb NP• Spin around ostium NP
MCC along lateral wall
MCC post uncinectomy
MCC at maxillary antrostomy
MCC at MT post part resect
MCC post concha resection
MCC post anterior ethmoidectomy
MCC post ant/post ethmoidectomy
MCC at sphenoidotomy
Mucus Flow
• Synechiae slow transport to lateral wall
• R vs L may show different pattern, despite same surgery
• Flow around, not over, obstructions
• Stasis noted in up to 30%
• Unoperated middle turbinate may show stasis
• Recirculation phenomenon
Measurement
• In Vitro• Mucus analysis
• frog palate, oscillating sphere magnetic rheometer, capillary viscometer, Searle system, controlled stress technique
• Quraishi, Clin Otolaryngol 1998
• Ciliary beat frequency (CBF)• photoelectric, laser scatter, visual counting (phase contrast
microscopy)
Measurement: in vitro
• Sampling• nasal brushing
• nylon brush or calgi swab
• for ultrastructural studies
• cup forceps biopsy• continuous layer of cells with basal layer
• nasal surgery• whole turbinate specimens
Measurement: in vivo
• In Vivo• Mucociliary wave frequency
• light scattering instrument
• Mucus transport time • aluminum discs(G), radioactively-tagged resin particles(G),
graphite(G), dye(S/G), saccharin test(S/G)
• S=sol layer, G=gel layer
Measurement: in vivo
• Saccharin time (ST)(MTT, MTR)• pharmaceutical grade saccharin (?)• medial side of inferior turbinate, 1 cm back• 1 mm saccharin on ring curette• swallow Q 30 sec.; no nose blowing/snuffling• 1st taste sweet=end test• stop at 30 or 60 min. if not (+) and place on tongue to
confirm ability to taste• Meta analysis of available literature: 13 min. mean ST
Cmejrek, OHNS 2005
Saccharin Test
Saccharin Test
Saccharin Test
Natural ostium Accessory ostium
Selected disorders affecting MCC
• Primary ciliary dyskinesia (PCD)• Ciliary disorientation (CD)
• Cystic fibrosis
• Young’s syndrome
• Allergic rhinitis
• Chronic rhinosinusitis
• Viral rhinitis
Primary Ciliary Dyskinesia
• Autosomal recessive
• 1:15 - 30,000 in population
• Symptoms begin shortly after birth
• Chronic sinusitis & bronchiectasis
• Immotile sperm
• Kartagener’s = same + situs inversus
Li, Drugs 2007
Primary Ciliary Dyskinesia
• Ultrastructural abnormalities• Dynein arm defect
• Radial spoke defect
• Abnormal length
• Management• Medical: ATB, chest
percussion
• Surgical: PE tubes (?), sinus surgery
Ciliary Disorientation
• Clinically appear as PCD
• Absent MCC
• Normal CBF/axoneme/mucus
• Mean ciliary orientation:• Disoriented: 23.30
• Normal: 12.80
Rayner, Am J Resp Crit Care Med, 1996
Bertrand, Acta Oto 2000
Ciliary Disorientation
=angle
Ciliary Disorientation
• Reversible if due to chronic upper resp tract infection (viral or bacterial)
• Noted in asthma and bronchitis
• Irreversible cases treated as PCD
• CD a better correlate of poor MCC than reduced CBF or abnl ciliary ultrastructure
Rayner, Am J Resp Crit Care Med 1996
Christmas, ENT J 2007
Cystic Fibrosis
• Autosomal recessive• 1/2500 live Caucasian
births• Defective CFTR (Cystic Fibrosis
Transmembrane Conductance Regulator)
• Poor chloride permeability
• Sodium hyperabsorbtion
• Desiccate mucus
• Tissue edema
Cystic Fibrosis
• Sx: chronic airway infect, exocrine pancreatic insufficiency, abnormal sweat, urogenital dysfunction
• Dx: clinical, sweat, genetic
• Tx: ATB, PP&D, DNAse, dependant sinus surgery (?)
Young’s Syndrome
• Adult onset
• Unknown etiology
• Sx: sinusitis, bronchiectasis, obstructive azoospermia
• Normal ciliary ultrastructure
• No CD at base, CD noted at tips• secondary to abnormal mucus?
de Iongh , Thorax, 1992
Allergic Rhinitis
• Transient increased CBF acutely• Increased CBF: leukotrienes (C4) & D4
• Altered rheologic properties & quantity of mucus (increase submucosal glands)
• Cyrus, OHNS 1998
• Chronic depression of MCC• Late effects of inflammation on rheology
• Nathan, JACI 2005
Chronic Rhinosinusitis
• Some debate as to effect• CBF incr
• 15.9 Hz (normals) 16.6 Hz (77% of CRS subjects)• Nuutinen, Arch Otol H&N 1993
• Most agree MCC worsened• Occluded OMC + bacteria = significant decrease CBF &
increase MTT• CBF & MTR normalized 6 wk. post middle meatal
antrostomy• Czaja, A J Rhinol 1998
Chronic Rhinosinusitis
• CBF reduction organism specific• Decr: H. influenza, P. aeruginosa, S. epidermidis,
Mycoplasma p.• Unchanged: S. pneumonia, M. catarrhalis
• Nuutinen, Arch Otol H&N 1993
• Toremalm, Eur J Respir Dis 1985
• Step pneumo > bacteroides:• # of ciliary ultrastructural changes
• Toskala, Acta Otolaryngol 1997
Chronic Hyperplastic Rhinosinusitis(CRSwNP)
• Polyps cause no significant decrease in CBF & MCC
• If MCC worsened, then likely due to mucus changes
• Slater, Clin Otolaryngol 1995
Viral URI
• MCC• Worsened by 120 post innoculation• Maximal decrease by 3 days• Slowed at 9 - 11 days
• Ultrastructural changes per EM• 3 day: no change• 1 week: few cilia remain• 3 week: regenerating cilia, normal orient
Rautiainen, Ann Otol Rhinol Laryngol 1992
Conclusion
• Innate nasal mucosal defense plays an important role in health
• Mucociliary clearance is a complex and vital function of respiratory epithelium
• Multiple processes that derange MCC can cause disease