Protective Properties of Inhaled IL-22 in a Model
of Ventilator-Induced Lung Injury
Sandra Hoegl1,2, Malte Bachmann2, Patrick Scheiermann1, Itamar Goren2, Christian Hofstetter3,
Josef Pfeilschifter2, Bernhard Zwissler1, and Heiko Muhl2
1Clinic for Anesthesiology, University Hospital of Ludwig-Maximilians-University, Munich, Germany;2Pharmazentrum Frankfurt/Zentrum fu ¨r
Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES), University Hospital Goethe–University Frankfurt, Frankfurt am Main, Germany;
and3Institute of Anesthesiology and Critical Care, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany
High-pressure ventilation induces barotrauma and pulmonary
inflammation, thus leading to ventilator-induced lung injury (VILI).
IL-22 has both immunoregulatory and tissue-protective properties.
Functional IL-22 receptor expression is restricted to nonleukocytic
cells, such as alveolar epithelial cells. When applied via inhalation,
IL-22 reaches the pulmonary system directly and in high concentra-
tions, and may protect alveolar epithelial cells against cellular stress
and biotrauma associated with VILI. In A549 lung epithelial cells,
IL-22 was able to induce rapid signal transducer and activator of
diated stable suppressor of cytokine signaling (SOCS) 3 expression
VILI, the prophylactic inhalation of IL-22 before induction of VILI
(peak airway pressure 5 45 cm H2O) protected the lung against
biotrauma (i.e., pulmonary concentrations of macrophage inflam-
matory protein–2, IL-6, and matrix metalloproteinase 9) and medi-
ated pulmonary STAT3/SOCS3 activation. In addition, despite
a short observation period of 4 hours, inhaled IL-22 resulted in an
improved survival of the rats. These data support the hypothesis
that IL-22, likely via activation of STAT3 and downstream genes
(e.g., SOCS3), is able to protect against cell stretch and pulmonary
baro-/biotrauma by enhancing epithelial cell resistibility.
IL-22 is a newly described member of the IL-10 family of
cytokines that is predominantly produced by activated T and
natural killer (NK) cells, but, due to restricted receptor
expression, specifically acts on the nonleukocytic cell com-
partment, in particular epithelial cells (1, 2). Evidence is
accumulating that IL-22 must be regarded a key T helper cell
type 17 signature cytokine (3–5). IL-22 appears to play
a pivotal role in host defense associated with bacterial in-
fections (6, 7), and has been implicated in the pathogenesis of
some chronic inflammatory diseases, such as rheumatoid
arthritis (8) and psoriasis (9). However, IL-22 apparently
mediates janus-faced functions in pathophysiology. In fact,
early studies identified IL-22 as being tissue protective in T
cell–mediated hepatitis (5, 10). Moreover, IL-22 ameliorates
the course of disease in murine models of inflammatory bowel
disease (11), and increases transepithelial resistance to injury
in gram-negative murine pneumonia (6). Those protective
functions of IL-22 are supposed to be predominantly mediated
by activation of the transcription factor, signal transducer and
activator of transcription (STAT)–3, a key component of
signal transduction engaged by IL-22 (2).
Life-saving mechanical ventilation is a major pillar of in-
tensive care medicine, but is, nevertheless, frequently associated
with severe adverse effects characterized by symptoms of acute
lung injury (barotrauma) and inflammation (biotrauma). Par-
ticularly in patients with severe respiratory failure, mechanical
ventilation is often associated with structural lung damage,
induction of proinflammatory cytokines, and increased mortal-
ity (12, 13).
Although pathophysiological mechanisms at the root of
ventilator-induced lung injury (VILI) still remain insufficiently
characterized, involvement of distinct cytokines in deleterious,
as well as in protective, principles must be assumed (14). The
hypothesis that modulating the balance between pro- and anti-
inflammatory cytokines will affect the outcome of disease is
supported by animal models demonstrating amelioration of
VILI associated with the blockage of key proinflammatory
cytokines, namely, IL-1 (15) or TNF-a (16). Moreover, our
group previously demonstrated that anti-inflammatory IL-10
reduces lung injury and mortality in experimental VILI (17),
likely by limiting pulmonary biotrauma.
Activation and perturbation of alveolar epithelial cells by
mechanical stretch obviously plays a key role in the patho-
physiology of VILI (13). Because IL-22 is known to specifically
act on cells of epithelial origin, and appears to show tissue-
protective potential at host–environment interfaces, we set
out to investigate effects of inhaled IL-22 in a rat model of
MATERIAL AND METHODS
IL-6, IL-10, IFN-g, and IL-22 (human) were from TEBU-BIO/
Peprotech Inc. (Frankfurt, Germany). IL-22 (rat) was pur-
chased from R&D Systems (Wiesbaden, Germany).
IL-22 is member of the IL-10 family of cytokines that
specifically acts on the nonleukocytic cell compartment—in
particular, epithelial cells. The role of IL-22 in inflamma-
tory processes differs depending on the affected tissue and
the type of inflammation. High-pressure ventilation can
cause structural and functional disturbances in the lung,
with subsequent release of proinflammatory mediators,
termed ventilator-induced lung injury. In this context, the
direct and high-dose intrapulmonary application of the
immunomodulatory cytokine, IL-22, per inhalation may be
an attractive therapeutic concept.
(Received in original form December 4, 2009 and in final form March 23, 2010)
This work was supported by a grant of the medical faculty of the Goethe-
University Frankfurt (‘‘Patenschaftsmodell/Tandemstipendium’’).
Correspondence and requests for reprints should be addressed to Sandra Hoegl,
M.D., Clinic for Anesthesiology, University Hospital of Ludwig-Maximilians-
University, Marchioninistrasse 15, D-81377 Munich, Germany. E-mail: sandra.
Am J Respir Cell Mol Biol
Originally Published in Press as DOI: 10.1165/rcmb.2009-0440OC on May 12, 2010
Internet address: www.atsjournals.org
Vol 44. pp 369–376, 2011
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