The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis?

Abstract

Chronic lung disease in humans is frequently complicated by the development of secondary pulmonary hypertension, which is associated with increased morbidity and mortality. Hypoxia, inflammation and increased shear stress are the primary stimuli although the exact pathways through which these initiating events lead to pulmonary hypertension remain to be completely elucidated. The increase in pulmonary vascular resistance is attributed, in part, to remodelling of the walls of resistance vessels. This consists of intimal, medial and adventitial hypertrophy, which can lead to encroachment into and reduction of the vascular lumen. In addition, it has been reported that there is a reduction in the number of blood vessels in the hypertensive lung, which could also contribute to increased vascular resistance. The pulmonary endothelium plays a key role in mediating and modulating these changes. These structural alterations in the pulmonary vasculature contrast sharply with the responses of the systemic vasculature to the same stimuli. In systemic organs, both hypoxia and inflammation cause angiogenesis. Furthermore, remodelling of the walls of resistance vessels is not observed in these conditions. Thus it has been generally stated that, in the adult pulmonary circulation, angiogenesis does not occur. Prompted by previous observations that chronic airway inflammation can lead to pulmonary vascular remodelling without hypertension, we have recently shown, using quantitative stereological techniques, that angiogenesis can occur in the adult pulmonary circulation. Pulmonary angiogenesis has also been reported in some other conditions including post-pneumonectomy lung growth, metastatic disease of the lung and in biliary cirrhosis. Such angiogenesis may serve to prevent or attenuate increased vascular resistance in lung disease. In view of these more recent data, the role of structural alterations in the pulmonary vasculature in the development of pulmonary hypertension should be carefully reconsidered.

Fig. 1

Photomicrographs showing intra-acinar pulmonary blood vessels (v) from (a) a rat lung in which chronic airway infection had been induced by inoculation of Pseudomonas aeruginosa in agar beads, (b) lung inoculated with sterile agar beads alone, and (c) lung that had not been inoculated. Sections were stained with Miller's stain, which shows elastin as blue, and counter stained with haematoxylin to demonstrate nuclei. Note well-developed tunica media in chronically infected lungs with an internal and external elastic lamina, whereas no tunica media is seen and there is a single elastic lamina in non-inoculated lung and in lung inoculated with sterile agar beads. Scale bar = 40 μm in all panels. (Figure reproduced with permission from Hopkins et al. Journal of Applied Physiology, 91: 919–928, 2001.)

Fig. 2

Immunoperoxidase staining of endothelial NOS in control lungs, and in lung with chronic airway infection following inoculation with Pseudomonas aeruginosa in agar beads. (a) Photomicrograph showing staining of eNOS in endothelium of blood vessel of control lung and patchy staining in alveolar walls (blue-black colour). (b) Photomicrograph showing absence of staining of eNOS in endothelium of blood vessel of Pseudomonasinoculated lung. All original magnifications ×380. (Figure reproduced with permission from Cadogan et al. American Journal of Physiology, 277: L616–627, 1999.)

Fig. 3

Mean (± SEM) reduction in wall tension in response to increasing concentrations of acetylcholine (ACh) in preconstricted pulmonary arterial rings isolated from control (n = 9) and chronically infected (n = 6) rats. Asterisk indicates significant difference between the two groups (P < 0.05, ANOVA).

Fig. 4

The mean (± SEM) total length of intra-acinar pulmonary blood vessels in the left lungs of normal control lungs (n = 8), lungs with chronic airway infection following inoculation with Pseudomonas aeruginosa in agar beads (n = 10), and lungs inoculated with sterile agar beads alone (n = 6). Asterisk indicates significant difference from noninoculated and placebo-inoculated groups (P < 0.05, ANOVA). (Figure reproduced with permission from Hopkins et al. Journal of Applied Physiology, 91: 919–928, 2001.)

Fig. 5

The mean (± SEM) number of branch-points of intraacinar pulmonary blood vessels in the left lungs of control rats (n = 8), lungs with chronic airway infection following inoculation with Pseudomonas aeruginosa in agar beads (n = 10), and lungs inoculated with sterile agar beads alone (n = 6). Asterisk indicates significant difference from noninoculated and placebo-inoculated groups (P < 0.05, ANOVA). (Figure reproduced with permission from Hopkins et al. Journal of Applied Physiology, 91: 919–928, 2001.)