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

Abstract

PurposeAlthough 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 methodsMale 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.ResultsPulmonary 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.ConclusionIn this rodent model of acute lung injury after repeated pulmonary lavage, AT2 receptor stimulation attenuates pulmonary inflammation but does not improve gas exchange.

Renin-angiotensin-system, a potential pharmacological candidate, in acute respiratory distress syndrome during mechanical ventilation

“…In line with this, a study by Imai and colleagues showed that Agtr2-knockout mice had more severe pathology in response to acid aspiration induced lung injury than wild-type controls [34]. A number of beneficial actions of AT2R in lung injury have recently been demonstrated [52][53][54]. Bruce and colleagues found that treatment with C21, an AT2R non-peptide agonist, ameliorates pulmonary fibrosis and prevents right ventricular fibrosis in pulmonary hypertension, and these beneficial effects are abolished by co-administration of the AT2R antagonist, PD123319 [52].…”

Structural alterations and markers of endothelial activation in pulmonary and bronchial arteries in fatal asthma

“…Endothelin-1 (ET-1), a potent vasoconstrictor, is involved in a pathway of tobacco-induced vascular dysfunction in smokers [15], and it is considered a mediator of asthma [16]. Angiotensin II type 2 receptor (AT2) has been described as protective against vasoconstriction, proliferation and fibrosis in models of acute lung injury and bronchodysplasia [17, 18], but there is no information about the expression of AT2 in the lungs of asthma patients.…”

Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to Macrophage Activation Syndrome: Therapeutic implications

“…For example, the blockade of AT1R improve CXCL16 angiogenic properties and decreased the monocyte and lymphocyte cellularity and activation [ 94 ]. In addition to CXCL16, The beneficial effects of a selective AT2R agonist were associated with the decreased recruitment or infiltration of macrophages in the lungs, reduced lung inflammation [ 160 ], diminished pulmonary collagen accumulation and improved cardiopulmonary complications through the downregulation of CCL2, IL-6, and TLR4 [ 161 ].…”