Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury.
ABSTRACT 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.
- SourceAvailable from: Adel Galal El-shemi
- Gastroenterology 01/2011; 140(5). DOI:10.1016/S0016-5085(11)61657-0 · 13.93 Impact Factor
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ABSTRACT: The chronic airway disease asthma causes significant burden to patients as well as the healthcare system with limited options for prevention or cure. Inadequate treatment strategies are most likely due to the complex heterogeneous nature of asthma. Furthermore, the severe asthma phenotype is characterized by the lack of a response to standard medication, namely, corticosteroids. In the last several years it has been shown that the eosinophilic/atopic phenotype of asthma driven by T(H)2 mechanisms is not the only immunologic pathway contributing to disease. In fact, there has been evidence revealing that severe asthmatics in particular have neutrophilic inflammation, and this is associated with corticosteroid resistance. T(H)17 cells, a recently discovered lineage of T helper cells, play an important role in lung host defense against multiple pathogens via production of the cytokine IL-17. IL-17 promotes neutrophil production and chemotaxis via multiple factors. Mouse and human studies provide robust evidence that T(H)17 cells and IL-17 play a role in severe asthma and may contribute to corticosteroid resistance. As we learn more about T(H)17 cells in severe asthma, the goal is to potentially target this pathway for treatment in the hope of significantly improving the quality of life for those children and adults affected with this disease. This article is part of a Special Issue entitled: Biochemistry of Asthma.Biochimica et Biophysica Acta 02/2011; 1810(11):1066-79. DOI:10.1016/j.bbagen.2011.02.002 · 4.66 Impact Factor