Prophylactic and therapeutic approaches to acute lung injury, targeting alveolar epithelial type II cells

Abstract

could be accelerated, and have found that rolipram, a phosphodiesterase (PDE)-IV inhibitor, enhanced the growth of cultured AEC-II without infl uence on fi broblasts [2]. The enhancing effects of rolipram and KGF/ HGF were additive. Further studies are required to confi rm the clinical effi cacy of the drug in enhancing AECII proliferation. However, because pulmonary fi brosis is the main cause of death in the late phase of ALI, it is important to prevent fi brotic changes of the lung in response to various insults by inhibiting fi bloblast proliferation. Of interest is the observation that culture of lung fi broblasts in the presence of AEC-II can minimize fi broblasts growth through a mechanism mediated by prostaglandin E2. In the progress of ALI, the apoptosis of AEC-II contributes to extensive destruction of the alveolar epithelial architecture. Therefore, we assessed the effects of various drugs that are often used perioperatively on the endotoxin-induced apoptosis of cultured primary rat AEC-II. We observed that a clinically relevant concentration of propofol inhibited AEC-II apoptosis. Rolipram also had this action. The acid-base balance condition of the culture medium is thought to infl uence AEC-II apoptosis. In our experiment using cultured A549 cells, an AEC-II-like cell line, hypocapnic alkalosis potentiated the hydrogen peroxide-induced apoptosis of A549 cells and caspase activation, although an acidifi ed medium did not change the oxidativeinduced apoptosis of the A549 cells. Anesthetists have recently focused much attention on ventilatory management to prevent the exacerbation of lung damage in ALI. In several animal experiments, hypocapnic alkalosis has been recognized to worsen ALI induced by reactive oxygen species (ROS). Thus, the enhancement of AEC-II apoptosis by hypocapnic alkalosis may be responsible for hyperventilation-induced deterioration in ALI. Another plausible therapeutic strategy for ALI is to prevent the suicide of AEC-II. We must emphasize that AEC-II, as well as being victims in the pathogenesis of ALI, also act as attackers. In response to various Alveolar epithelial type II cells (AEC-II) play an important role in the repair of alveolar epithelium because of their differentiation into alveolar epithelial type I cells (AEC-I). In acute lung injury (ALI), various infl ammatory mediators produced in the lung attack AEC-II, leading to extensive loss of the alveolar epithelium. We discuss potential therapeutic approaches to ALI, targeting AEC-II. The basic concept of our strategy lies in the restoration of the quantity and function of AEC-II. Several growth factors (e.g., keratinocyte growth factor [KGF], and hepatocyte growth factor [HGF]) are known to potentiate AEC-II proliferation in both in vitro and in vivo systems. However, the clinical application of the growth factors does not seem feasible, because of their high cost. As an alternative to the administration of these agents, therefore, adenovirus-mediated KGF gene transfer into AEC-II has been attempted experimentally, with success [1]. For the same purpose, we have sought a simple pharmacological modality by which AEC-II proliferation