EXPERIMENTAL THERAPIES FOR HYPOXIC PULMONARY VASOCONS TRICTION

Abstract

We read with great interest the review article of Morrell et al. (1), describing experimental therapies for hypoxia-induced pulmonary hypertension during acute lung injury. The authors give an excellent overview of the available experimental treatment strategies in this setting, such as inhaled nitric oxide (NO), and explored potential therapeutic avenues associated with the inhibition of rho kinase. The authors also examined the use of phosphodiesterase 5 inhibitors and combination therapy in the treatment of hypoxic pulmonary vasoconstriction. Hypoxic pulmonary vasoconstriction is a vascular feedback mechanism by which ventilation/perfusion (Va/VQ) mismatch is minimized. Due to vasoconstriction of pulmonary vessels in hypoventilated hypoxic lung areas, blood flow is redistributed away from poorly ventilated lung areas to better oxygenated alveoli, thereby preventing hypoxemia. This physiological reflex was first described by von Euler and Liljestrand in 1946 (2). When the alveoli become hypoxic, the arterioles constrict. Thus, under normal circumstances, the blood entering the pulmonary veins contains only oxygenated blood. The pulmonary vascular smooth muscle cell is electrically negative because Na+ is pumped out of the cell and K+ is pumped in. K+ can leak out, but Na+ cannot go back in. With hypoxia, the permeability to K+ is decreased. As less K+ leaves the cell, it depolarizes and becomes permeable to Ca++. Ca++ enters the cell, actinomyosin is activated, and the cell contracts. Thus, the pulmonary smooth muscle cells of hypoxic alveoli are constricted (3). Amino acids are transported into the vascular endothelial cells through several transporters, l-arginine (ARG) by the cationic Y transporter. Then ARG is converted into citrulline by the constitutive endothelial cell NO synthase. NO diffuses to the pulmonary vascular muscle where it combines with guanylate cyclase to form cyclic guanosine monophosphate. This, in turn, results in the removal of Ca++ from the cell and relaxation. During hypoxia, there is a depression of the Y transporter. Thus, without ARG, NOS does not produce NO, and vasoconstriction occurs (4). In addition, there is the inducible NO synthase isoform which is upregulated in the airway columnar epithelial cells. Inducible NO synthase forms NO at a rate some 1,000 times more than endothelial cell NO synthase; NO gas is released into the airway and passes into the ventilated alveoli. The ventilated NO contributes to respiratory homeostasis by dilating the vessels of the ventilated alveoli as well as relaxing the airway smooth muscle. In patients who have to be intubated because of hypoxia, we affect the homeostatic NO by intubation because we block the entry of NO into the lower lung from the upper airway. During hyperventilation, we not only lower their Paco2, we also drop their Pano. Consequently, hyperventilated patients should have a greater pulmonary vascular resistance. Inhaled NO has shown to reduce pulmonary vascular resistance with selectivity to the pulmonary circulation and a short half-life, but inhaled NO also has adverse side effects, such as methemoglobinemia. In addition, the use of inhaled NO produces high costs and requires a complicated delivery system (1). The inhalation therapy with NO is controversially discussed; during shock state, NO can combine with superoxide (O2−) and form reactive nitrogen species, such as peroxynitrite (ONOO−), which may lead to cell damage and DNA destruction (5). The interaction between NO and ARG is in a sensitive balance, which once disturbed, either by hypoxia or NO treatment, can lead to a deteriorated pulmonary function. Yu et al. (6) have shown an enormous turnover of ARG in severely burned patients. Importantly, Xia et al. (7) demonstrated that NO synthase generates O2− in ARG-depleted cells, leading to cellular injury. The metabolism of ARG might play a major role in future investigations, especially in burn patients suffering from hypoxia from smoke inhalation.