Recombinant human ACE2: acing out angiotensin II in ARDS therapy

Acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disorder that is frequently associated with multiple organ dysfunction leading to high mortality. The mechanisms underlying ARDS are multifactorial, and are thought to include the reninangiotensin system (RAS) [1, 2]. The RAS is a coordinated complex hormonal cascade that is composed of angiotensinogen, angiotensinconverting enzyme (ACE) and its homolog angiotensin converting enzyme 2 (ACE2), and angiotensin II (Ang II) type 1 and type 2 receptors (AT1, AT2). ACE cleaves the decapeptide Ang I into the octapeptide Ang II, while ACE2 cleaves a single residue from Ang II to generate Ang 1-7, which in turn blocks Ang II and inhibits ACE [3]. Thus, the ACE2 axis negatively regulates the ACE axis. Great attention has been focused on the role of the RAS in blood pressure homeostasis and cardiovascular function, but there is also increasing interest in understanding the pathophysiological role of the RAS in lung. While only 20% of capillary endothelial cells in all other organs, including the heart, express ACE, it is detectable in the entire capillary network of the alveoli in human lung [4]. Therefore, conversion of Ang I to Ang II can readily occur in the lung by abundant ACE in pulmonary vessels. This may contribute to rapid responses of vasoconstriction in the pulmonary circulation and low blood flow, leading to ventilation/perfusion mismatch in conditions such as tissue hypoxia. On the other hand, ACE2 is primarily produced in Clara cells and type II alveolar epithelial cells [5] and epithelial injury is a critical event in the development of ARDS in humans; thus, the ability to produce ACE2 is severely impaired, resulting in dominant ACE activities during ARDS and/or ventilatorinduced lung injury (VILI) [1, 6]. Increasing evidence has emerged that reactive oxygen species (ROS), especially nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and hydrogen peroxide (H2O2), act as upstream regulators of RAS and ACE activity in various cells and tissues [7]. The RAS in turn induces production of ROS that function as intracellular and intercellular second messengers to modulate many downstream signaling cascades. In normal conditions, the interplay between the ROS and RAS is important in maintaining pulmonary function and integrity. Under ARDS and VILI conditions, this vicious cycle feedback loop contributes to lung injury and remodeling through oxidative damage [6, 8]. Midkine (MK), a heparin-binding growth factor, has been recently demonstrated as a novel modulator of RAS in the context of ARDS and VILI [6]. The plasma concentration of MK increased dramatically in patients with ARDS [6], and an up-regulation of MK in lung epithelial cells is reported in response to cyclic mechanical stress [6]. Exposure to MK protein results in an enhanced ACE expression in primary human lung cells [9]. MK has been shown to stimulate the RAS by acting as an upstream signaling molecule of Ang II and mediates lung–kidney crosstalk leading to development of RASassociated fibrosis [9]. The RAS—specifically Ang II via AT1 and AT2 receptors—has a number of effects: (1) induction of pulmonary vasoconstriction and vascular permeability in response to hypoxia resulting in pulmonary edema; (2) stimulation of the lung production of inflammatory cytokines directly and indirectly by targeting bradykinin; (3) acceleration of the Fas-induced apoptosis in alveolar * Correspondence: zhangh@smh.ca Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Room 619, LKSKI, 30 Bond Street, Toronto, ON M5B 1W8, Canada Interdepartmental Division of Critical Care Medicine, Departments of Anesthesia and Physiology, University of Toronto, Toronto, ON, Canada