Airway Obstruction Plays Role in ALI

In addition to the transudate formed as a result of the leaky bronchial microvasculature, there is also a marked secretion from the airway mucous glands. The airway secretions contain mucins and blood coagulation factors such as fibrinogen. Broncho-pulmonary epithelial cells and alveolar macrophages express tissue factor when they are activated, which contributes to fibrin clots (Figure 1).

There are several reasons that the airway cast formation should be avoided. First of all, airway obstruction causes ventilation-perfusion mismatching. As a consequence of airway obstruction, some parts of the lung are ventilated but some are not. The blood flow to the nonventilated part will be a shunt flow. Second, if the patients are under mechanical ventilation, the tidal volume of air goes only into the ventilated part of lung. When the ventilator is volume controlled, it causes a significant increase in airway pressure. From our experience, histological investigation showed less than 10 percent obstruction in noninjured sheep bronchi or bronchioles, but after smoke inhalation with burn injury or smoke inhalation with pneumonia, the obstructed area significantly increased to 30 to 40 percent of the area [6]. The sheep with elevation in airway pressure showed marked increases in mRNA for the chemokine IL-8 in the pulmonary microcirculatory area, along with evidence of neu-trophil infiltration. In order to prevent barotrauma to the lung, we put the animals with ALI on a CO2 removal device, which allows a reduction in tidal volume and ventilatory pressures. Those animals showed significantly lower expression of IL-8, suggesting that the overextension of the airways is involved in chemokine induction and further inflammatory reactions. Perhaps this was the result of reduced cast formation. On the other hand, more than 90 percent of the bronchial venous drainage flows directly into the pulmonary microvasculature. Leukocytes activated in the airway as well as other materials such as ROS, RNS, or proteases would be directly transported to the pulmonary microvasculature.

Another strategy to reduce airway cast formation is to prevent an increase in bronchial blood flow. As described earlier, the bronchial blood flow increases tenfold to fifteen-fold after injury; the increase of blood flow causes the increase in vascular permeability, which results in cast formation. Ablation of the bronchial circulation is reported to prevent the ovine model of ALI [7], suggesting that the blood flow through bronchial artery plays a role in the pathophysiology. Since upregulation of nitric oxide causes an increase in blood flow, the inhibition of NOS is effective to prevent cast formation. From our study in sheep, both the inhibition of iNOS and that of nNOS was effective in reducing cast formation [4, 5]. However, these NOS inhibitors did not completely block cast formation. We have not investigated the effect of dual inhibition of iNOS and nNOS. The effect might be additive. This hypothesis should be confirmed. There is much debate over whether or not mice have a blood supply from the bronchial artery, but still we do not have the exact answer. Thus gene-modified mice such as iNOS and/or nNOS knockout are not suitable for this type of study.

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Essentials of Human Physiology

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