Although permissive hypercapnia improves the prognosis of patients with acute respiratory distress syndrome, it has not been conclusively determined whether hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of the lung. The present study was designed to explore the molecular mechanism of HA in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial cells. LPS elicited degradation of inhibitory protein kappaB (IkappaB)-alpha, but not IkappaB-beta, resulting in activation of nuclear factor (NF)-kappaB in human pulmonary artery endothelial cells. Exposure to HA significantly attenuated LPS-induced NF-kappaB activation through suppressing IkappaB-alpha degradation. Isocapnic acidosis and buffered hypercapnia showed qualitatively similar but quantitatively smaller effects. HA did not attenuate the LPS-enhanced activation of activator protein-1. Following the reduced NF-kappaB activation, HA suppressed the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin-8, resulting in a decrease in both lactate dehydrogenase release into the medium and neutrophil adherence to LPS-activated human pulmonary artery endothelial cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis would have anti-inflammatory effects essentially through a mechanism inhibiting NF-kappaB activation, leading to downregulation of intercellular adhesion molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to pulmonary endothelial cells.

A small GTPase, Rho, plays key roles in cell adhesion, motility, and contraction after stimulation. Among Rho effectors isolated, the family of Rho-associated coiled-coil-forming protein kinases (ROCK) is implicated in Rho-mediated cell adhesion and smooth muscle contraction. The effect of a specific inhibitor of ROCK, Y-27632, was evaluated in a murine model of acute lung injury induced by intravenous injection of Escherichia coli endotoxin (lipopolysaccharide [LPS]). Lung edema was evaluated by measuring extravascular leakage of radio-labeled serum albumin, and neutrophil emigration into the lung parenchyma by morphometric observation and measuring myeloperoxidase activity. Pretreatment with Y-27632 attenuated both lung edema and neutrophil emigration after LPS. We also measured albumin transfer through cultured endothelial cell monolayers on a porous filter. Tumor necrosis factor-␣ significantly increased albumin transfer, which was attenuated by pretreatment with Y-27632. Fluorescence microscopy revealed that morphologic changes in endothelial cells induced by tumor necrosis factor-␣ were inhibited by Y-27632. In contrast, the increased fraction of neutrophils with polymerized actin after formyl-methionyl-leucyl-phenylalanine was not altered by Y-27632. These data suggest that ROCK may play an important role in the pathogenesis of LPS-induced lung injury and that ROCK inhibition could attenuate cytoskeletal rearrangement of endothelial cells, leading to decreased neutrophil emigration into the lung parenchyma.

To evaluate the ability of high-resolution computed tomography (HRCT) to detect longitudinal changes in structural abnormalities caused by smoking, HRCT and pulmonary function tests were used to examine nonsmokers, current smokers, and past smokers annually for 5 yr. Inspiratory HRCT was taken for the upper, middle, and lower lung fields, while expiratory images were obtained for the upper and lower lung fields only. We estimated the three quantitative CT parameters including MLD (mean CT value), HIST (CT value with the most frequent appearance), and %LAA (relative area of low attenuation with CT values less than -912 HU). Most of the pulmonary function tests, excepting FEV(1), did not change annually, whereas many of the inspiratory HRCT parameters did. In nonsmokers, only %LAA in the middle or lower lung fields exhibited an annual increase. In current smokers, %LAA in the upper lung field was augmented, while inspiratory MLD or HIST in the middle or lower lung field became more positive. In past smokers, %LAA in any lung field examined increased. The annual change in %LAA in the upper lung field was larger for past smokers than nonsmokers, with little difference between past and current smokers. Expiratory CT parameters showed few annual changes in all groups. In conclusion, (1) aging increases airspace abnormalities, mainly in the lower lung field; (2) although continuous smoking worsens airspace abnormalities mainly in the upper portion of the lung, this trend does not seem to slow down even after smoking cessation; and (3) inspiratory HRCT images are superior to expiratory images for longitudinal estimation of structural abnormalities caused by aging and smoking.

These results suggest that BMS is safe and useful to monitor pulmonary biochemical events in ARDS.