Supplement
Supplement
Atemwegs- und Lungenkrankheiten, Jahrgang 37, 1. Supplement 2011, S. S1–S5
The surfactant system – a new approach for
treating the upper respiratory tract mucosa
A. Glowania1,2, R. Mösges3, M. Böhm3, A. Knopf4 and L. Klimek1
1Center
for Rhinology and Allergology, Wiesbaden, 2Mannheim ENT University
Hospital, 3Institute for Medical Statistics, Informatics and Epidemiology, University
of Cologne, 4ENT Clinic, Rechts der Isar Hospital, TU Munich
Key words
surfactant – phospholipid – liposomes – rhinitis
– sinusitis
Schlüsselwörter
Surfactant – Phospholipid – Liposomen – Rhinits
– Sinusitis
Background
Across the whole respiratory system, at
least 2 liters of secretory products are produced within 24 hours by the mucous membranes and glands located therein. As the
beginning of the airways, the nose has many
functions to fulfill in addition to conditioning
the air that we breathe, with nasal secretion
in particular thereby being indispensable for
mucociliary transport and mucosal defense.
Every day, approximately 12,000 liters of
air passes through the nose of an adult. The
nasal mucous membrane is exposed to large
quantities of gases, aerosols and particles in
the process. Studies have been able to demonstrate that approximately 90 – 95% of all
particles larger than 15 µm in diameter are
deposited in the nose. Pollens, for example,
are 15 – 200 µm in size on average [1]. The
nasal mucous membrane therefore needs to
have an effective self-cleaning and defense
system, which shall be looked at more closely in the following.
Liquid film and mucociliary
transport
Symposium, 6th German
Allergy Congress 2011,
Wiesbaden
© 2011
Dustri-Verlag Dr. Karl Feistle
ISSN 0341-3055
DOI 10.5414/ATX01743
Mucociliary transport constitutes one of
the most important properties of the respiratory mucous membrane. This continuous
transport of secretory products is brought
about by the cilia attached to the epithelial
cells, which, through constant beating, propel the film of liquid on the surface of the
epithelial cells in the direction of the pharynx. This effect is also referred to as a selfcleaning system.
The classical model was assumed to have
a 2-layer film of liquid: the respiratory epi-
thelium is covered by a superficial and highly viscous layer of mucus (gel phase), underneath which is a low-viscosity aqueous layer
of fluid (sol phase), which is in direct contact
with the epithelial cells.
Per ciliated epithelial cell, approximately
2,000 cilia beat at a rate of 10 – 30 Hz in the
periciliary sol phase. The ciliary beat consists
of a rapid effective stroke, which straightens
the cilia, thereby bringing the outstretched
ciliary tips into contact with the mucus in the
gel phase, as well as a slow recovery stroke,
where the bent cilia return to their starting
position in the sol phase. The mucus in the
gel phase is transported in one direction by
this motion sequence [3, 4, 5].
From what we know today, the classical
model needs, however, to be modified somewhat. It can be assumed that surfactant can
be found at the sol phase-gel phase interface
in the form of an osmiophilic membrane (bilayer), which has the task of making it easier
for the gel phase to glide on the sol phase.
At the air-liquid interface, the gel phase
is covered by a surfactant film (surfactant:
surface active agent), which, at irregular intervals, can have multiple layers (multilayers), but not the same number thereof [6, 7,
8].
Surfactant composition
A mixture comprising various substances, synthesized primarily in Type II pneumocytes in the lungs, but also in the epithelial
cells and glandular cells of the air passages,
is referred to as surfactant.
It consists of 90% lipids, 90% of which
is, in turn, made up of various phospholipids.
Saturated and unsaturated forms of phos-
S2
Glowania, Mösges, Böhm, Knopf and Klimek
Several properties are attributed to the
surfactant in the air passages. It improves
mucociliary transport by accelerating ciliary
beat frequency and by conditioning the viscosity of the mucus [6].
Even more important in this context, as
described in the beginning, is the fact that, by
reducing surface tension, surfactant changes
the quality of mucus, which has a considerable impact:
Figure 1. Schematic representation of the motion
of a single cilium. a) Effective stroke; b) recovery
stroke.
Figure 2. To begin with, the film of liquid, which
moistens and protects the mucous membrane
is stabilized as a result and prevented from
rupture. In addition, especially the phospholipids of the surfactant are responsible for the
forces that act on inhaled particles and draw
Structure of the liquid film.
phatidylcholine make up the majority of the
phospholipids.
The remaining 10% of surfactant is composed of proteins, with 4 surfactant-specific
proteins (SP-A, SP-B, SP-C and SP-D) having been thereby identified in addition to serum proteins [7].
While the existence of surfactant and its
importance in relation to the lower respiratory tract, particularly in the alveoli, has long
been known, investigations of upper respiratory tract surfactant, especially as part of the
liquid film in the nose and paranasal sinuses,
have only been intensified in recent years [9,
10, 11, 12].
Importance of surfactant
At alveolar level, its role as a so-called
“surface-active factor” lies in reducing the
surface tension of the alveolar liquid film of
the alveoli. When the alveoli become smaller
upon breathing out, the surfactant film thickens on their surface, thereby preventing alveolar collapse.
Figure 3. Surfactant layer on the gel phase.
them into the liquid film. When an inhaled
particle comes into contact with the liquid
film of the air passages and thus with the surfactant film, surface forces between deposited particles and the surfactant film lead to
(partial) wetting of the particle. The change
in the particle surface by surfactant components causes the particle to be displaced into
the liquid phases and thus directed to the muciliary clearance process [6, 7].
The surfactant system – a new approach for treating the upper respiratory tract mucosa
Figure 4. Impaired surfactant causes the liquid
film to rupture.
S3
(phospholipids), the hydrophilic parts (“head
group”) of which face the aqueous side.
In line with the new therapy concept, liposomes made of phosphatidylcholine are
applied in nasal spray form. The applied
phospholipids are to stabilize and complement the surfactant film, as shown schematically in Figure 7.
The effectiveness of this drug-free treatment concept, which has been outlined here
in theory, has already proved successful in
practice in relation to various indications, as
demonstrated by numerous study results and
field reports.
Within the context of this summary, the
following paragraphs are to provide a brief
overview of the treatment range for liposomes. Kindly refer to the respective publications for further details.
Allergic rhinitis
Figure 5. Missing liquid film with exposed and unprotected mucosal epithelial cells.
This natural defense and self-cleaning
system only works when the surfactant film
is unimpaired. Should this not be the case,
the liquid film situated beneath the surfactant
threatens to rupture, as a result of which the
mucous membranes are rendered unprotected and exposed to direct physical forces (e.g.
heat and cold), harmful substances as well as
to viral pathogens.
On the basis of these findings, an important goal of treatment has to be the restoration and stabilization of surfactant and, associated with this, the continuous dispersal
of the whole liquid film, which is needed, in
turn, to keep the body’s own self-cleaning
and defense system working.
A new therapy approach in this context is
the substitution of the major surfactant component with phospholipid-liposomes.
Liposomes are phosphatidylcholine vesicles, i.e. spherical encapsulated lamellar
lipid membranes. They possess an aqueous
interior, separated by a continuous aqueous
phase. The membrane consists of a double
lipid layer (bilayer) of amphiphilic lipids
Mucosal barrier disturbance plays a major role in the development of allergic conditions. Various studies have already been
able to demonstrate that nasal application to
the inflamed mucous membrane effectively
reduces the symptoms of seasonal allergic
rhinitisis (SAR) [13, 14, 15].
With the help of a nasal provocation test,
one pilot study was able to demonstrate that
symptomatic treatment with a liposomal nasal spray leads to a significant improvement
in allergic symptoms [13].
A comparative study demonstrated that
treatment with a liposomal nasal spray leads
to a significant reduction in symptoms as
well as to an improvement in the quality of
life of patients and does not significantly
vary thereby from guideline antihistamine
and glucocorticoid spray therapy, although
guideline combination therapy was used during the study twice as often [14].
Given that many patients are extremely
skeptical of cortisone treatment and have a
phobia of steroids, whether justified or not,
the new therapy concept constitutes a pertinent non-pharmacological alternative for the
treatment of allergic rhinitis.
S4
Glowania, Mösges, Böhm, Knopf and Klimek
Sjögren’s syndrome
Figure 6. Image of a liposome with lipid bilayer
membrane.
Sjögren’s syndrome constitutes the most
common rheumatic condition involving the
head and neck region and is characterized by
marked dryness symptoms affecting the eyes
and the upper aerodigestive tract. Severe
complications in the form of troublesome
and sometimes painful swallowing, impaired
smell and taste, caries, periodontosis and inflammation of the salivary glands are linked
to the dryness symptoms. Subjective complaints can be eased significantly through the
use of nasal, eye and mouth sprays, which
are based on phospholipid-liposomes. The
saliva interleukin 6 concentration, as a possible surrogate parameter for autoimmune
inflammation, was lowered significantly in
the high-risk group after only two months
treatment with the phospholipid-liposome
products.
Future prospects
Chronic sinusitis
Figure 7. Schematic representation of the treatment concept.
Rhinitis atrophicans
Atrophic rhinitis involves degeneration
and the destruction of the cell structures of
the respiratory epithelium. In addition to
symptoms such as recurrent infections as
well as cephalalgia, impaired smell and the
formation of crusts, it leads to a significant
reduction in the quality of life of those affected.
The use of a topical phosphatidyl solution led, on an individually attempted treatment basis, to a significant improvement in
findings on the one hand and to a clear drop
in nasal obstruction and head and face pains
on the other. Further studies are needed in order to confirm the findings obtained.
The initial results of a comparative study
investigating the treatment of patients with
chronic sinusitis show that the treatment
concept with phospholipid-liposomes is also
effective in this commonly occurring condition [17].
Rhinitis sicca
The results of the comparative study investigating the treatment of rhinitis sicca
demonstrate the good efficacy of the liposomal nasal spray compared to established
therapeutic agents [18].
Rhinitis medicamentosa
The theoretical approach would suggest
that using the liposomal nasal spray would
be of benefit. Field reports are not yet available.
The surfactant system – a new approach for treating the upper respiratory tract mucosa
Literatur
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
Klimek L. Aufbau und Funktion des oberen Respirationstrakts. In: Saloga J, Klimek L, Buhl R,
Mann W, Knop J (Hrsg). Allergologie-Handbuch, Grundlagen und klinische Praxis. Stuttgart:
Schattauer, 2006.
Rasp G. Physiologie und Immunologie der Nasenschleimhaut. In: Grevers G (Hrsg). Praktische
Rhinologie. München: Urban und Schwarzenberg; 1998, 1-15.
Stannard W, O’Callaghan C. Ciliary function and
the role of cilia in clearance. J Aerosol Med. 2006;
19: 110-115.
Baroody FM. Mucociliary transport in chronic
rhinosinusitis. Clin Allergy Immunol. 2007; 20:
103-119.
Antunes MB, Gudis DA, Cohen NA. Epithelium,
cilia, and mucus: their importance in chronic
rhinosinusitis. Immunol Allergy Clin North Am.
2009; 29: 631-643.
Gehr P, Green FHY, Geiser M, Im Hof V, Lee MM,
Schürch S. Airway surfactant, a primary defense
barrier: mechanical and immunological aspects. J
Aerosol Med. 1996; 9: 163-181.
Gehr P, Im Hof V, Geiser M, Schürch S. The mucociliary system of the lung – role of surfactants.
Schweiz Med Wochenschr. 2000; 130: 691-698.
Bachofen H, Gerber U, Gehr P, Amrein M,
Schürch S. Structures of pulmonary surfactant
films adsorbed to an air-liquid interface in vitro.
Biochim Biophys Acta. 2005; 1720: 59-72.
Woodworth BA, Smythe N, Spicer SS, Schulte BA,
Schlosser RJ. Presence of surfactant lamellar bodies in normal and diseased sinus mucosa. ORL J
Otorhinolaryngol Relat Spec. 2005; 67: 199-202.
Schlosser RJ. Surfactant and its role in chronic
sinusitis. Ann Otol Rhinol Laryngol Suppl. 2006;
196: 40-44.
Woodworth BA, Neal JG, Newton D, Joseph K,
Kaplan AP, Baatz JE, Schlosser RJ. Surfactant
protein A and D in human sinus mucosa: a preliminary report. ORL J Otorhinolaryngol Relat
Spec. 2007; 69: 57-60.
Ji X, Wang Q, Xie J, Yang K. Measurement of
components of the phospholipid of the surfactant
in irrigating fluid from the nasopharynx of patients with chronic sinusitis. Lin Chung Er Bi Yan
Hou Tou Jing Wai Ke Za Zhi. 2007; 21: 63-66.
Meyer-Gutknecht H, Mösges R. Wirkung eines
neuartigen liposomalen Nasensprays auf die
Symptome der saisonalen allergischen Rhinitis.
HNO kompakt. 2008; Suppl 1: 1-5.
Weston LA, Mösges R. Behandlung der saisonalen allergischen Rhinokonjunktivitis mit einem
liposomalen Nasenspray. Allergologie. 2010; 33:
196-204.
Böhm M, Avgitidou G, El Hassan E, Mösges R.
Liposomes: a new non-pharmacological therapy
concept for seasonal-allergic-rhinoconjunctivitis.
Eur Arch Otorhinolaryngol. 2011 (Epub ahead of
print).
Kaschke O. Auswirkungen einer Steroidphobie in
Deutschland auf die Therapie mit topischen Glukokortikoiden. MedReport. 2008; 32: 10.
Eitenmüller A, Piano L, Böhm M, Glowania A,
Klimek L, Mösges R. Verträglichkeit und Auswirkungen auf die Lebensqualität durch die Be-
S5
handlung mit einem liposomalen Nasenspray bei
Patienten mit chronischer Sinusitis. Allergo J.
2011; 20: S55.
[18] Hahn C, Mösges R, Böhm M. Vergleich der Verträglichkeit und der Auswirkungen auf die Lebensqualität der Behandlungsmethode mit einem
liposomalen Nasenspray gegenüber der Anwendung Dexpanthenol-haltiger Nasensalbe bzw.
Isotonem NaCl-Spray bei Patienten mit Rhinitis
sicca. Allergo J. 2011; 20: S53.
A. Glowania
Facharzt für Hals-Nasen-Ohrenheilkunde
Zentrum für Rhinologie und
Allergologie Wiesbaden
An den Quellen 10
D–65183 Wiesbaden
e-mail: [email protected]