Protective Properties of Inhaled IL-22 in a Model of Ventilator-Induced Lung Injury

Clinic for Anesthesiology, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
American Journal of Respiratory Cell and Molecular Biology (Impact Factor: 3.99). 05/2010; 44(3):369-76. DOI: 10.1165/rcmb.2009-0440OC
Source: PubMed


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 concentrations, 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 transcription (STAT)-3 phosphorylation/activation, and hereon mediated stable suppressor of cytokine signaling (SOCS) 3 expression detectable even 24 hours after onset of stimulation. In a rat model of VILI, the prophylactic inhalation of IL-22 before induction of VILI (peak airway pressure = 45 cm H(2)O) protected the lung against pulmonary disintegration and edema. IL-22 reduced VILI-associated biotrauma (i.e., pulmonary concentrations of macrophage inflammatory protein-2, IL-6, and matrix metalloproteinase 9) and mediated 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.

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    • "Socs3 is a cytokine-inducible negative regulator of cytokine signalling with established anti-inflammatory and anti-apoptotic effects [38], [39]. Socs3 was shown to contribute to lung protection after IL-22 challenge in a model of VILI [24]. Atf3 is critical for the prevention of acute inflammatory syndromes, including VILI, by limiting pro-inflammatory cytokine expression and may control the balance between proliferative and apoptotic signals [22], [40]. "
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    ABSTRACT: Recently, we have shown that inhalation of hydrogen sulfide (H2S) protects against ventilator-induced lung injury (VILI). In the present study, we aimed to determine the underlying molecular mechanisms of H2S-dependent lung protection by analyzing gene expression profiles in mice. C57BL/6 mice were subjected to spontaneous breathing or mechanical ventilation in the absence or presence of H2S (80 parts per million). Gene expression profiles were determined by microarray, sqRT-PCR and Western Blot analyses. The association of Atf3 in protection against VILI was confirmed with a Vivo-Morpholino knockout model. Mechanical ventilation caused a significant lung inflammation and damage that was prevented in the presence of H2S. Mechanical ventilation favoured the expression of genes involved in inflammation, leukocyte activation and chemotaxis. In contrast, ventilation with H2S activated genes involved in extracellular matrix remodelling, angiogenesis, inhibition of apoptosis, and inflammation. Amongst others, H2S administration induced Atf3, an anti-inflammatory and anti-apoptotic regulator. Morpholino mediated reduction of Atf3 resulted in elevated lung injury despite the presence of H2S. In conclusion, lung protection by H2S during mechanical ventilation is associated with down-regulation of genes related to oxidative stress and inflammation and up-regulation of anti-apoptotic and anti-inflammatory genes. Here we show that Atf3 is clearly involved in H2S mediated protection.
    PLoS ONE 07/2014; 9(7):e102401. DOI:10.1371/journal.pone.0102401 · 3.23 Impact Factor
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    • "Besides aforementioned tissue protective modes, this specific function of IL-22 is based on strengthening of the anti-bacterial arsenal at host/environment interfaces by mechanisms that likely include upregulation of anti-bacterial peptides such as β-defensins, lipocalin, or RegIIIβ/γ, amplification of anti-bacterial inducible nitric oxide synthase (iNOS), and enhanced epithelial mucus production (Ziesché et al., 2007; Aujla and Kolls, 2009; Blaschitz and Raffatellu, 2010; Mühl et al., 2011; Sonnenberg et al., 2011; Eddens and Kolls, 2012). Induction of SOCS proteins (Nagalakshmi et al., 2004; Hoegl et al., 2011) and of anti-inflammatory IL-10 (Nagalakshmi et al., 2004) by IL-22 may additionally be crucial for fine-tuning local inflammation at epithelial sites of tissue damage. Altogether, IL-22 appears pivotal for stabilization of epithelial integrity and homeostasis upon injurious, noxious, and infectious challenge. "
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    ABSTRACT: Interleukin (IL)-10 and IL-22 are key members of the IL-10 cytokine family that share characteristic properties such as defined structural features, usage of IL-10R2 as one receptor chain, and activation of signal transducer and activator of transcription (STAT)-3 as dominant signaling mode. IL-10, formerly known as cytokine synthesis inhibitory factor, is key to deactivation of monocytes/macrophages and dendritic cells. Accordingly, pre-clinical studies document its anti-inflammatory capacity. However, the outcome of clinical trials assessing the therapeutic potential of IL-10 in prototypic inflammatory disorders has been disappointing. In contrast to IL-10, IL-22 acts primarily on non-leukocytic cells, in particular epithelial cells of intestine, skin, liver, and lung. STAT3-driven proliferation, anti-apoptosis, and anti-microbial tissue protection is regarded a principal function of IL-22 at host/environment interfaces. In this hypothesis article, hidden/underappreciated pro-inflammatory characteristics of IL-10 and IL-22 are outlined and related to cellular priming by type I interferon. It is tempting to speculate that an inherent inflammatory potential of IL-10 and IL-22 confines their usage in tissue protective therapy and beyond that determines in some patients efficacy of type I interferon treatment.
    Frontiers in Immunology 02/2013; 4:18. DOI:10.3389/fimmu.2013.00018
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    • "In contrast, IL-22 has protective functions in models of microbe/infection-driven inflammation at host/environment interfaces [14-16], likely by up-regulating anti-microbial peptides [3-5,14,15], inducible nitric oxide (NO) synthase [17,18] and mucus production [16]. The tissue protective properties of IL-22 also extend to experimental ventilator-induced lung injury [19] and, in particular, to specific models of hepatic diseases [5]. "
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    ABSTRACT: Background Interleukin-22 (IL-22), recently identified as a crucial parameter of pathology in experimental liver damage, may determine survival in clinical end-stage liver disease. Systematic analysis of serum IL-22 in relation to morbidity and mortality of patients with advanced liver cirrhosis has not been performed so far. Methods This is a prospective cohort study including 120 liver cirrhosis patients and 40 healthy donors to analyze systemic levels of IL-22 in relation to survival and hepatic complications. Results A total of 71% of patients displayed liver cirrhosis-related complications at study inclusion. A total of 23% of the patients died during a mean follow-up of 196 ± 165 days. Systemic IL-22 was detectable in 74% of patients but only in 10% of healthy donors (P < 0.001). Elevated levels of IL-22 were associated with ascites (P = 0.006), hepatorenal syndrome (P < 0.0001), and spontaneous bacterial peritonitis (P = 0.001). Patients with elevated IL-22 (>18 pg/ml, n = 57) showed significantly reduced survival compared to patients with regular (≤18 pg/ml) levels of IL-22 (321 days versus 526 days, P = 0.003). Other factors associated with reduced overall survival were high CRP (≥2.9 mg/dl, P = 0.005, hazard ratio (HR) 0.314, confidence interval (CI) (0.141 to 0.702)), elevated serum creatinine (P = 0.05, HR 0.453, CI (0.203 to 1.012)), presence of liver-related complications (P = 0.028, HR 0.258, CI (0.077 to 0.862)), model of end stage liver disease (MELD) score ≥20 (P = 0.017, HR 0.364, CI (0.159 to 0.835)) and age (P = 0.011, HR 0.955, CI (0.922 to 0.989)). Adjusted multivariate Cox proportional-hazards analysis identified elevated systemic IL-22 levels as independent predictors of reduced survival (P = 0.007, HR 0.218, CI (0.072 to 0.662)). Conclusions In patients with liver cirrhosis, elevated systemic IL-22 levels are predictive for reduced survival independently from age, liver-related complications, CRP, creatinine and the MELD score. Thus, processes that lead to a rise in systemic interleukin-22 may be relevant for prognosis of advanced liver cirrhosis.
    BMC Medicine 09/2012; 10(1):102. DOI:10.1186/1741-7015-10-102 · 7.25 Impact Factor
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