Sugar Consumption Increases Susceptibility to Allergic Airway Inflammation and Activates the Innate Immune System in the Lung

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Introduction:
Obe s i t y is ari s k factor for asthma with the st ro ng e s t corre l a ti o n shown in children.
In children, the frequent intake of foods and drinks whic h are high ins ugar might be the
initiation of poor di etary habi ts, whi ch directly rel a te to overall health, body mass index,
physical activity and secondary pathologies like type II diabetes and cardio-vascular
diseas es.
Interactions between molecular and cellular components of the pulmonary inn a t e
immune system such as th e carbohydrate reco g niti o n mol ecule surfactant protein-D
(SP -D) and dendritic cells may reg ul ate susceptibility to airway inflammatory diseases.
The objec tive of this study was to investigate how hi g h sugar intake and subsequent
intermittent hy p e rg l yc e m i a , affects allergic sensitization, allergic ai rw a y inflammation
and airway res p on s i v en es s .
Hypothesis:
Materials and Methods:
Results:
Summary:
§SP-D-/- mice have elevated bl o o d gl u c os e levels and show sig n s
of constitutive activation of the innate immune syst em .
§Intermittent hyperglycaemia (IH) can be induc ed in mice wi thou t
confining effects res u l tin g from adiabetic or obese phenotype.
§IH res u l te d in enhanc ed inflammatory re s po nse in allergen
sensitized and challenged animals.
§Up-regu l at i on of SP-D, which is no r m a l l y associated wi t h the
res o l ut i on of the ai r w a y inflammation, was abrogated in IH allergen
chall enged mice.
Conclusions:
Gl uc o s e mi ght compete for the CRD bi nding site of SP-D in a
concentration-dependent manner and subsequently inhibit the
CRD-mediated functions of SP-D.
The lack of the immunosupressive effect of SP-D seems to create a
pro-inflammatory environment and confer increased susceptibility
to allergic sensitization.
Funding:This s tudy was funded by R0 1 A I 055 59 3 -01
Methods:
Mice (C57Bl / 6, SP- D-/-) were sen sitized intraperitoneally (i.p. ) on days 0and 14 and
chal len g ed intranasally (i.n .) on day 28 with Asp ergi ll us fu mig atus (A f) and groups of
n=6were stu di ed 0(n on ch all en g ed) , 12,24,48,and 96 hours later.
To induceintermittend hyperglycaemi a (IH) mi c e received 5 % su cro se sol uti on instead of
drinking water at days of sensi ti sat io n an d chal l en ge.
Cell u la r infiltration an d rel e as e of pro-inflammatory cyto ki n e s was assessed by an aly sis
of bronchoalveolar lavag e (BAL) fluid and differen tial cell cou nt s were done on
cyto cen tri fu g e preparations from BAL fluids.
West ern blot or ELI SA fo r SP- D was performed using an in-house polyclonal an ti -SP-D
ant i bo d y.Specific binding was vi su ali z ed by en han c ed ch e mil u min es cen ce with ECL
Kit .
1) Naïve SP- D kn oc ko ut mi ce have incr eased blood
glucose levels, significantly mor e BAL APC s an d
elevat ed TNFα
2) Sugar feeding in du ced int er mitten t hyperglycaem ia but
had no eff ect on body weight
4) Sugar consu mp t ion during the sen sitiz at ion period
resulted in eosinop hilic inflammation and AHR
3) Sugar consu mp t ion incr eased the numb er of ant ig en
presenting cells and eo sin op h ils in the BAL
Sugar consumption increases susceptibility to allergic airway inflammation
and activates the innate immune system in the lung
Sonja Kiers tein1,2,Kateryna Krytska1, Gerold Kierstein1, László Hortobágyi1, Angela Haczku1,
1Divisions of Pulmonary, Allergy and Critical Care, University of Pennsylvania, Philadelphia, PA, 2Nestlé Research Center, Lausanne, Switzerland
SIRPa
SP-D
Inhibition of APC in r esting lung
by S P -D
APC
Calreticulin
(CD 91)
Glucose bound to
SP-D‘s CRD
Pro-
inflammatory
mediators
APC
Impairm ent of the im m unoprotectiv e effects
of S P -D by glucose
Intermittent hy perglyc emia
negativel y affects
the pulmonary immune system.
i.p.i.p. i.n.
0 7 13 14 24
Sucrose
Days
0 1 12 Days48 96 10
Hou rs
Af Af Af
SP-D protein lev els i nc reased after allergen chall enge of s ensitized
mice. However, no up-regu lat ion of SP-D was observed in mice
with suc ros e-induced intermittent hyperglycaemia (IH).
0n 12 24 48 96 Naive Af 36h IH-Af 36h
SP-D
5) Sugar co n sumpti on inhibit ed the protective up-
regulation of SP-D following allerg en chal lenge
BAL T NFale vels
16
12
8
4
0
Nai v e Af (12 h)
pg/ml
Water
Sucros e **
80
160
220
Bloodglucose Bloodglucose Body weight
MCh (mg/ ml)
IH/Af mice had increased lev e ls of TNFacompared to con tr ol s .
Dietary sucrose induced an early rec ru i tm ent of APCs in sensitized
mice and re s ul t ed in increased eosinophilia after allergen challenge.
SP-D-/- mice have almost doubled bl ood gluc ose levels compared to
wt animals .We also observed asignificantly hi gher number of APCs
in the BAL and increased levels of TNFain naïve mice.
SP-D+/+ SP-D-/-
**
7.8% 27.9%
SP-D-/-miceWild-type m i ce
BAL TNF-a
pg/ml
BAL cells
**
**
SP-D+/+ SP-D-/-
SP-D+/+ SP-D-/-
Sucrose consumption induced transient increases of blood gluc ose
levels.Si n c e the mice had anormal insulin re s p onse , there was no
significant effec t on the overall blood gl u c os e levels and no wei ght
gain was obs erved compared to control animals.
Sensitized mi c e on sugar diet developed an eosinophilic inflammation
and AHR without specific all e r g e n challenge.