Download Potential role for lipopolysaccharide in congenital sensorineural

Journal of Medical Microbiology (2010), 59, 377–383
Review
DOI 10.1099/jmm.0.015792-0
Potential role for lipopolysaccharide in congenital
sensorineural hearing loss
A. L. Smit,1 R. J. Stokroos,1 S. G. H. Litjens,2 B. Kremer1,3
and B. W. Kramer3,4
Correspondence
A. L. Smit
[email protected]
1
Department of Otorhinolaryngology/Head and Neck Surgery, Maastricht University Medical
Centre, PO Box 5800, Maastricht, The Netherlands
2
Faculty of Health, Medicine and Life Sciences, University of Maastricht, PO Box 616, Maastricht,
The Netherlands
3
School of Oncology and Developmental Biology, University of Maastricht, PO Box 5800,
Maastricht, The Netherlands
4
Department of Pediatrics, Maastricht University Medical Centre, PO Box 5800, Maastricht, The
Netherlands
Congenital sensorineural hearing loss (SNHL) is common. In the Western world, the incidence is
1–3 per 1000 live births. The aetiology encompasses genetic and non-genetic factors accounting
for 55 % and 45 % of cases, respectively. Reports that describe the contribution of intrauterine
infection to the occurrence of congenital SNHL are limited, and comparative analysis of the
different pathogens is lacking. Lipopolysaccharide (LPS), a product of bacteriolysis, has been
demonstrated to be associated with inner ear damage in experimental studies. To elucidate the
potential role of this toxin in congenital SNHL and to identify the pathogenesis and transmission
routes, we reviewed the literature. We speculate that different routes of exposure to LPS in utero
may result in congenital inner ear damage.
Introduction
Congenital sensorineural hearing loss (SNHL) in childhood is common. In the Western world, the incidence
amongst full-term live births amounts to 1–3 per 1000
(Davis et al., 1995; Erenberg et al., 1999; Mencher, 2000;
Nance et al., 2006). In preterm infants, the incidence is
even higher, with 2–4 per 100 live births (Erenberg et al.,
1999). The aetiology of congenital SNHL is attributable to
genetic and non-genetic factors in 55 % and 45 % of cases,
respectively (Nance et al., 2006). Non-genetic causes are
diverse, e.g. perinatal exposure to hypoxia (Abramovich
et al., 1979), acidosis (Marlow et al., 2000), otoxicity of
drugs such as aminoglycoside or loop diuretics (Young &
Magnum, 2007) and viral or bacterial infections (Gross
et al., 2000). In this review, we will focus on the infectious
causes of congenital SNHL, of which infection with
cytomegalovirus (CMV) is the most common (Nance
et al., 2006). The estimated prevalence of CMV infection
amounts to 0.2–2.2 % of all live births (Ludwig & Hengel,
2009; Mussi-Pinhata et al., 2009). Ten to twenty per cent of
infants congenitally infected with CMV had varying
degrees of hearing loss at birth (Katano et al., 2007).
Besides CMV, other micro-organisms, e.g. Toxoplasma
gondii, measles virus, mumps virus, varicella-zoster virus,
parvovirus B19, herpes simplex virus, Treponema pallidum
and rubella virus, have been identified to cause unilateral
015792 G 2010 SGM
or bilateral congenital SNHL, which may be temporary or
permanent, with or without loss of vestibular function
(Gross et al., 2000; Wild et al., 1989).
Bacterial products leading to SNHL are the subject of
increasing interest. Lipopolysaccharide (LPS) is released
from the outer wall of Gram-negative bacteria such as
Escherichia coli and Neisseria spp. after bacteriolysis
(Darrow et al., 1992). This bacterial endotoxin consists of
a lipid A, a core polysaccharide and an O antigen and is
known for its multiple effects on biological systems, e.g.
induction of inflammation and the modulation of the
immune responses (Darrow et al., 1992). It is also associated with functional and morphological inner ear damage
in experimental animal models (Guo et al., 1994; Watanabe
et al., 2001, 2002), which we will discuss in the next
paragraph. We hypothesize that this toxin, by means of an
intrauterine infection, can play a role in the pathogenesis of
congenital SNHL.
LPS-induced functional and morphological inner
ear changes
By discovering LPS in middle ear effusions in chronic otitis
media (Bernstein et al., 1980; DeMaria et al., 1984; Iino
et al., 1985), attention was drawn to its crucial role in the
onset of SNHL. Subsequent functional studies did
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A. L. Smit and others
demonstrate an elevation of hearing level thresholds after
LPS exposure. Comis et al. (1991) and Tarlow et al. (1991)
revealed early onset SNHL within 2 h after LPS application
into the guinea pig inner ear by cochlear potential
measurement. In a similar model, high frequency losses
were observed by auditory brainstem response measurement within 1 (Guo et al., 1994) or 2 (Darrow et al., 1992)
days after LPS application. A gradual improvement of
responses was seen after a 5 day interval to near baseline
level by 28 days (Darrow et al., 1992).
To explain the LPS-related functional impairment of the
inner ear, several morphological temporal bone studies
were designed using different animal models. These
findings are summarized in Table 1. Comis et al. (1991)
and Tarlow et al. (1991) showed loss of hair bundles of
inner and outer hair cells as well as swelling of the tectorial
membrane directly after LPS application into the inner ear
of guinea pigs. Darrow et al. (1992) demonstrated in the
same species a dosage-dependent inflammatory reaction
with inflammatory cells in the perilymphatic spaces; lower
LPS dosages resulted in minimal inflammation during the
evaluation period of 7 days. Higher dosages showed a
higher degree of inflammation after 2–4 days which
resolved at day 7 (Darrow et al., 1992). Also the stria
vascularis revealed LPS-related alterations in the first days
after exposure (Guo et al., 1994). Watanabe et al. (1995)
demonstrated similar results after LPS application into the
middle ear. Moreover, neutrophil recruitment was seen by
myeloperoxidase staining in multiple cochlear structures
48 h after LPS exposure (Watanabe et al., 2001).
Other experimental animal models and application
schemes demonstrated analogous patterns of inflammatory
and structural changes within small variations of time of
onset. Within 12–72 h post middle ear application of LPS
in a chinchilla model, bleeding and inflammation in the
perilymphatic spaces and spiral ligament, strial swelling
and sensory cell degeneration were observed (Kawauchi
et al., 1989; Lim et al., 1990). Repeated application of LPS
at the round window niche of rats by Spandow et al. (1989)
resulted in hair cell loss within 2 weeks. Nakai et al. (1980)
observed similar results as well as a total disappearance of
outer hair cells and nerve fibres in the spiral lamina after a
period of 1.5 months (Nakai et al., 1980).
Pathogenesis of LPS-induced inner ear
dysfunction
LPS is known for its diverse effects on the inflammatory
cascade through activation of the Toll-like receptor 4
(TLR-4). These receptors are expressed in the inner ear by
immune cells such as macrophages and B cells, and
non-immune cells, including fibroblasts and epithelial
cells (Wang et al., 2006). TLR-4 signalling activates
nuclear factor kappa B, which is the ‘master switch’ for
inflammation-mediated cytokine production and release of
mediators such as nitric oxide (NO) (Mustafa et al., 1989;
Ramilo et al., 1989; Spandow et al., 1989; Watanabe et al.,
378
2000b). In the resulting network of pro- and antiinflammatory cytokines, interleukin-1 (IL-1), IL-2, tumour
necrosis factor alpha and transforming growth factor beta
are the most important cytokines and modulators for the
inflammatory response as well as for homeostasis and
tissue repair (Garcia Berrocal & Ramirez-Camacho, 2000;
Harris et al., 1997). Recent studies provided new insights
into the relationship between LPS and NO related potential
inner ear damage (Shi et al., 2003). NO has a role in
regulation of vascular tone, auditory transduction and
cochlear and vestibular neurotransmission (Fessenden &
Schacht, 1998; Hess et al., 1998; Morizono & Ikeda, 1990;
Takumida & Anniko, 2004a, b; Zdanski et al., 1994).
Besides this, NO has a dose-dependent action. In small
amounts, it has a defensive action against invading
organisms by inhibition of adhesion molecule expression,
cytokine and chemokine synthesis and leukocyte adhesion
and transmigration (Guzik et al., 2003; Liaudet et al., 2000;
Takumida et al., 2000). When produced in larger amounts,
NO can be injurious to healthy tissue such as cochlear cells
(Amaee et al., 1997; Forstermann et al., 1994; Iadecola et
al., 1995a, b; Jung et al., 2003; Schmidt & Walter, 1994;
Takumida et al., 2000) due to formation of peroxynitrite
(ONOO2) by reaction of NO with the superoxide anion
(O{
2 ) (Kastenbauer et al., 2001) (Fig. 1).
NO is synthesized by NO synthase (NOS). This enzyme has
different isoforms: constitutive and inducible NOS (cNOS
and iNOS) (Takumida & Anniko, 2004a). The neuronal
cNOS is always present and produces, depending on the
intracellular calcium levels, small amounts of NO. In
contrast, the iNOS isoform is usually absent, but can be
synthesized by virtually any cell type when adequately
stimulated by cytokines or LPS (Hess et al., 1999; Moncada
et al., 1991; Takumida et al., 2000; Takumida & Anniko,
2004a; Watanabe et al., 2000a, b, 2001). This LPS-mediated
elevation of iNOS was also demonstrated in the walls of
blood vessels of the cochlear lateral wall and in different
cells of the organ of Corti, including in stereocilia of inner
and outer hair cells, pillar cells, hair cell nerve fibres and in
marginal cells (Hess et al., 1999; Shi et al., 2003; Watanabe
et al., 2000a). By this mechanism, the formation of NO and
subsequent peroxynitrite could be responsible for the
described functional and morphological cochlear alterations
after LPS exposure of the inner ear.
In utero lesion of the inner ear
As discussed above, experimental studies have shown LPSinduced functional and structural inflammatory changes in
the inner ear. However, several pathways must be
considered to explain LPS-related in utero inflammatory
changes of the inner ear and subsequent potential
congenital SNHL.
Fetal inflammation is the consequence of a chorioamnionitis (Kramer et al., 2005b). This is defined as an
inflammation of the amniotic fluid and membranes
(Goldenberg et al., 2000). This inflammatory process is
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Potential role for LPS in congenital hearing loss
Table 1. Effects of LPS on the inner ear in experimental animal models
Reference
Animal model
LPS origin
Methods*
Evaluation time
after application
ResultsD
Degeneration of OHCs and IHCs
and stria vascularis.
Vacuolization and degeneration
of vestibular sensory cells;
vacuolization of dark cells.
OHC loss
Nakai et al.
(1980)
Mice
E. coli
Repeated intradermal
and intravenous
injection
3 days/1.5
months/3 months
Spandow et al.
(1989)
Kawauchi et al.
(1989)
Rat
E. coli
2 weeks
Chinchilla
Salmonella
typhimurium
Instillation into RW
niche
Instillation into
tympanic cavity
Lim et al.
(1990)
Chinchilla
Salmonella
typhimurium
Instillation into
tympanic cavity
12 h–3 weeks
Comis et al.
(1991); Tarlow
et al. (1991)
Darrow et al.
(1992)
Guo et al.
(1994)
Guinea pig
E. coli
Hours
Guinea pig
Guinea pig
Salmonella
typhimurium
E. coli
Watanabe et al.
(1995)
Guinea pig
E. coli
Perfusion in scala
tympani or injection
in CSF
Inoculation in scala
tympani
Perfusion into
perilymphatic space
via RWM
Intraperitoneal
injection and
application at RW
niche
Watanabe et al.
(2001)
Guinea pig
Not specified
Transtympanical
injection
2 days
Watanabe et al.
(2002)
Guinea pig
E. coli
Transtympanical
injection
2 days
12–72 h
1–7 days
1/3/5 days
2 days/1 day
Bleeding and inflammatory cell
recruitment in perilymphatic
space including the spiral
ligament, strial swelling and
sensory cell degeneration
Inflammatory infiltrates in the
scala tympani, vestibule and
spiral ligament, strial swelling,
and sensory cell degeneration
Damage cochlear hair cells,
swelling of the tectorial
membrane
Inflammatory infiltrates in
perilymphatic spaces
Damaged stria vascularis
Inflammatory cells in the endoand perilymphatic spaces, stria
vascularis, spiral ligament and
organ of Corti. Widened
intercellular spaces in the stria
vascularis. Bleeding in the endoand perilymphatic spaces.
MPO in the spiral ligament, stria
vascularis and supporting cells
of the organ of Corti
MPO in the sensory epithelium
and dark cell area
*CSF, cerebrospinal fluid; RW, round window; RWM, round window membrane.
DIHCs, inner hair cells; OHCs, outer hair cells; MPO, myeloperoxidase.
generally regarded as a continuum with early-stage
maternal neutrophils involved progressing to later stages
with a fetal neutrophil inflammatory reaction (Goldenberg
et al., 2000). Micro-organisms responsible for chorioamnionitis can reach the chorioamnion by the abdominal
cavity through the Fallopian tubes or inadvertent needle
contamination at the time of amniocentesis or chorionicvillus sampling, by passage through the cervix from the
vagina (Goldenberg et al., 2000; Romero & Mazor, 1988),
or transplacentally due to a maternal systemic infection
(Goldenberg et al., 2000) (Fig. 2). The micro-organisms or
the microbial products, once present in the amniotic fluid,
can gain access to the fetus (Goldenberg et al., 2000) and
evoke a local inflammatory response by entry via the
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respiratory tract, skin, gastrointestinal tract and ear (Lee et
al., 2007). When neutrophils infiltrate the umbilical cord
vessels (Sampson et al., 1997), this can be considered a
progression of a chorioamnionitis to a funisitis, which
results in a fetal systemic inflammatory response syndrome
(Lee et al., 2007; Yoon et al., 2000). This is associated with
increased morbidity and mortality of the fetus (Kramer
et al., 2005b, 2009b).
Once the inflammatory mediators or micro-organism enter
the fetus, several routes are possible for reaching the
labyrinth (Fig. 2). The upper respiratory tract as well as
passage of the tympanic membrane gives entry to the
middle ear. Subsequently, the oval and round window are a
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A. L. Smit and others
Fig. 1. Mechanisms leading to an LPS-related inflammatory
response of the inner ear and cell death through the action of
cytokines and NO.
porte d’entrée to the inner ear. The round window
membrane can be passed easily by small molecular mass
substances (Cureoglu et al., 2005; Goycoolea et al., 1988;
Goycoolea, 2001; Kawauchi et al., 1989; Spandow et al.,
1988; Trinidad et al., 2005) in contrast to large molecular
mass substances such as albumin or LPS (Goldberg et al.,
1981; Goycoolea et al., 1980; Spandow et al., 1988).
However, previous studies have demonstrated passage of
the toxin and cochlear inflammation by a suspected LPSrelated alteration of the membrane permeability or
structure (Cureoglu et al., 2005; Darrow et al., 1992;
Engel et al., 1995; Goycoolea et al., 1988; Juhn et al., 1989;
Kim & Kim, 1995; Morizono & Ikeda, 1990; Paparella et al.,
1970; Schachern et al., 1992; Spandow et al., 1988, 1989,
1990; Takumida & Anniko, 1998, 2004b; Trinidad et al.,
2005). Another option is a haematogenous route via blood
vessels of the inner ear (Watanabe et al., 2002), which are
mainly located in the spiral limbus and the lateral cochlear
wall (Kastenbauer et al., 2001; Li et al., 2008; Watanabe
et al., 2002). Previous findings after LPS exposure-related
damage in the endolymphatic compartment suggested
blood–labyrinth barrier disruption by the inflammatory
molecules and the capability of reaching the endolymph (Li
et al., 2008). This barrier may be even more permeable at
very early stages of development as shown in a rat model
(Suzuki et al., 1998). Also the permeability to proteins of
the blood–brain barrier is affected by LPS (Wang et al.,
2006). This can result in a third, neurogenic, route, in
which the infection could travel via meninges and along the
eighth cranial nerve through the modiolus to the spiral
ganglion and limbus (Klein et al., 2008; Li et al., 2008).
Besides this, propagation of infections from the cerebrospinal fluid to the peri- and endolymphatic space via the
cochlear aquaduct or endolymphatic duct, respectively, has
been observed (Klein et al., 2008; Li et al., 2008).
Role of LPS in congenital hearing loss
Regarding the described LPS-related functional and
morphological effects on the inner ear as well as the
presumed transmission routes, an association between an
LPS-induced chorioamnionitis and congenital inner ear
changes or congenital SNHL seems plausible. This is
supported by the findings of Suppiej et al. (2009), who
recently described a positive association between a
histological identified chorioamnionitis and SNHL in
childhood after preterm delivery before 32 weeks gestational age. They postulated a relationship with worse
neurological and cochlear development and maturation.
Fig. 2. Inflammatory pathways from the uterine compartment to the fetal inner ear.
380
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Journal of Medical Microbiology 59
Potential role for LPS in congenital hearing loss
However, it was not possible to determine whether preterm
histological chorioamnionitis in itself or the higher
exposure to other risk factors such as neonatal hypotension
had concomitant roles in this relationship with SNHL.
The presented studies demonstrating LPS-induced functional or morphological inner ear changes were done using
different experimental animal models and time intervals.
To what extent these changes can be extrapolated to the
human fetus has not been addressed so far. It is unclear
whether the described alterations are persistent or fluctuating in time or will recover in the long term with or
without removal of the stimulus. Moreover, the ototoxic
potential of LPS seems to be dependent on dosage, LPS
type (Darrow et al., 1992) and application method.
Intramuscular (Jobe et al., 2000), intraperitoneal (Newnham et al., 2002) and intravascular (Cock et al., 2002)
administration show more severe effects on the fetus (Jobe
et al., 2000; Nitsos et al., 2002) than intra-amniotic LPS
injection (Moss et al., 2003).
Previous studies in a sheep model did confirm the
hypothesis of mechanisms of maturation of the fetal
immune system in the case of repeated exposure to LPS
(Kallapur et al., 2007; Kramer et al., 2005a, 2007, 2009a;
Kramer, 2008). To what extent this will influence the
immunological response of the fetal inner ear to prolonged
in utero exposure to LPS is not clear. By designing a new
experimental animal model we hope to answer some of
these fundamental questions in the near future to elucidate
the role of LPS in and mechanisms of LPS-related
congenital SNHL after intrauterine fetal exposure. A better
understanding of the fetal health risks can play a role in
maternal screening programmes and could be a step
forward in the design of preventive strategies for congenital
SNHL or early clinical screening.
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