Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury

Journal of Inflammation Research, May 2018

Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury Mario Menk, Jan Adriaan Graw, Clarissa von Haefen, Hendrik Steinkraus, Burkhard Lachmann, Claudia D Spies, David Schwaiberger Department of Anesthesiology and Operative Intensive Care Medicine, Charité – University Medicine Berlin, FreieUniversität Berlin, Humboldt-Universitätzu Berlin, and Berlin Institute of Health, Germany Purpose: Although the role of the angiotensin II type 2 (AT2) receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21) might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange. Materials and methods: Male adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9), a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9), and a control group that received mechanical ventilation only (control, n=9). Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/dry-weight ratio of lungs was determined. Transcriptional and translational regulation of pro- and antiinflammatory cytokines IL-1β, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma. Results: Pulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6 expressions in the lungs, whereas the expressions of IL-1, IL-10, and IL-4 remained unchanged. During the 240-min observation period, AT2 receptor stimulation did not improve pulmonary gas exchange or lung edema. Conclusion: In this rodent model of acute lung injury after repeated pulmonary lavage, AT2 receptor stimulation attenuates pulmonary inflammation but does not improve gas exchange. Keywords: AT2 receptor, lung failure, ARDS, acute lung injury, Compound 21 (C21)

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Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury

Journal of Inflammation Research Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury 0 Department of Anesthesiology and Operative Intensive Care Medicine, Charité - University Medicine Berlin, FreieUniversität Berlin, Humboldt- Universitätzu Berlin, and Berlin Institute of Health , Germany 8 1 0 2 - l u J - 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s e r p .vdoew l.yno PowerdbyTCPDF(ww.tcpdf.org) Purpose: Although the role of the angiotensin II type 2 (AT2) receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21) might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange. Materials and methods: Male adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9), a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9), and a control group that received mechanical ventilation only (control, n=9). Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/ dry-weight ratio of lungs was determined. Transcriptional and translational regulation of proand antiinflammatory cytokines IL-1β, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma. Results: Pulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6 expressions in the lungs, whereas the expressions of IL-1, IL-10, and IL-4 remained unchanged. During the 240-min observation period, AT2 receptor stimulation did not improve pulmonary gas exchange or lung edema. Conclusion: In this rodent model of acute lung injury after repeated pulmonary lavage, AT2 receptor stimulation attenuates pulmonary inflammation but does not improve gas exchange. - factor-alpha (TNF-α).5–9 Clinically, the leading symptom is a rapid onset of arterial hypoxemia and/or hypercarbia which, in severe cases, can be life-threatening. Successful treatment strategies include mechanical ventilation with low tidal volumes, fluid-restrictive resuscitation strategies, and prone positioning of the patients.10–12 However, to date, no specific pharmacological treatment is available that targets the 180 underlying pulmonary inflammation during the development l-Ju2 or the clinical course of ARDS. -13 Animal studies have shown that pharmacological inhibion7 tion of pulmonary inflammation can lead to beneficial effects .026 in acute lung failure. In different experimental models, the .495 attenuation of pulmonary inflammation mitigated the alveolar .37 edema and subsequently improved arterial oxygenation.13,14 /yb Also, in a rodent model, inhalation of the antiinflammatory .com cytokine IL-10 not only lowered pulmonary inflammation, rsse but also attenuated lung damage and reduced mortality.15 In p humans, however, none of the pharmacological interven.vdoew l.yno tions tested so far has demonstrated any beneficial effects in /ww seu ARDS. Therapies found to be ineffective include inhalation :/ l ttsp ona of vasodilators, N-acetyl-cysteine, β2 agonists, surfactant, from rpeo statins, and others.16–20 h rs The renin–angiotensin–aldosterone system (RAS) plays daed F a major role in human physiology and is involved not only in lonw cardiovascular disease, but also in the regulation of inflamdo mation.21 The two main receptors of the RAS, namely the rcah AT1 receptor and the AT2 receptor, play an intricate and see dual role in inflammation. The AT1 receptor contributes itnoaRm twohetirsesausethdeamATa2gereccaeupstoedr ibsythuonucgohntttroohllaevde ibnefnlaemficmiaaltiaonnd, lfam protective effects.21,22 Overall, the AT2 receptor is regarded fIno as a counterpart to the AT1 receptor, antagonizing the lrna effects of AT1 receptor signaling. There is evidence that Juo the angiotensin-AT2-receptor-axis acts as an endogenous, tissue-protective system involved in the downregulation of inflammation and the promotion of tissue repair.23 Studies with the nonpeptide, specific, and selective AT2 receptor agonist Compound 21 (C21) demonstrated a marked inhibition of inflammatory signaling pathways by direct AT2 receptor activation.24 Based on its antiinflammatory properties, C21 could evoke beneficial effects in animal models of myocard (...truncated)


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Mario Menk, Jan Adriaan Graw, Clarissa von Haefen, Hendrik Steinkraus, Burkhard Lachmann, Claudia D Spies, David Schwaiberger. Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury, Journal of Inflammation Research, 2018, pp. 169-178, DOI: 10.2147/JIR.S160573