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.

Helper T-Cell Type 17 Cytokines and Immunity in the Lung

“…Moreover, recombinant IL-22 applied in the lung improves bacterial clearance (35). IL-22 has also been shown in a model of ventilator-induced lung injury to have potential therapeutic benefit (37). It has been shown that the lack of IL-22 is associated with reduced epithelial repair (38) and increased fibrosis (36) in experimental influenza infection.…”

Interleukin-22 Reduces Lung Inflammation during Influenza A Virus Infection and Protects against Secondary Bacterial Infection

“…IL-22 is also a key factor controlling mucosal immunity and the dissemination of commensal bacteria from the intestinal tract (22). In the lungs, IL-22 protects against experimental lung fibrosis (23) and ventilator-induced lung injury (24). IL-22 also limits Th2-mediated airway inflammation and tissue damage during asthma (25)(26)(27).…”

Mechanisms of Rapid Induction of Interleukin-22 in Activated T Cells and Its Modulation by Cyclosporin A

“…Once bound to its heterodimeric receptor, namely IL-22R1/IL-10R2, IL-22 will engage signal transduction dominated by activation of STAT3 (3) with subsequent context-specific amplification of anti-apoptotic, tissue protective, anti-bacterial, immunoregulatory, or proinflammatory genes. B cell lymphoma-2 and B cell lymphoma-xl (12), mucin-1 (13), ␤-defensins (14) and lipocalin (15), suppressor of cytokine signaling-3 (16), as well as CXCL8 (17), CXCL5, matrix metalloproteinase-3 (18), and iNOS (19) shall be quoted herein exemplarily. Immunoregulatory properties of IL-22 are likewise strictly context specific and range from protective functions seen in models of infection/microbe-driven inflammation (15,20), hepatitis (12), and ventilator-induced lung injury (16) to a clear pathogenic function seen in models of autoimmunity, specifically collagen-induced arthritis (21), and experimental psoriasis (22).…”