Increased pulmonary blood flow does not alter surfactant protein gene expression in lambs within the first week of life

Abstract

Neonates and infants with congenital heart disease with increased pulmonary blood flow suffer morbidity from poor oxygenation and decreased lung compliance. In a previous experiment involving 4-wk-old lambs with pulmonary hypertension secondary to increased pulmonary blood flow following an in utero placement of an aortopulmonary vascular graft, we found a decrease in surfactant protein (SP)-A gene expression as well as a decrease in SP-A and SP-B protein contents. To determine the timing of these changes, the objective of the present study was to characterize the effect of increased pulmonary blood flow and pulmonary hypertension on SP-A, -B, and -C gene expressions and protein contents within the first week of life. Of eight fetal lambs that underwent the in utero placement of the shunt, there was no difference in the expression of SP-A, -B, and -C mRNA levels or SP-A and -B protein contents compared with age-matched controls. The results showed that, in this model of congenital heart disease with pulmonary hypertension and increased pulmonary blood flow, the effect of the shunt on SP gene expression and protein content was not apparent within the first week of life.congenital heart disease AMONG NEONATES AND INFANTS with congenital heart disease with increased pulmonary blood flow, the presence of the systemicto-pulmonary communication often leads to progressive structural and functional changes in the pulmonary vascular bed, leading to pulmonary hypertension. The structural changes include increased muscularity of small pulmonary arteries with early distal extension, intimal hyperplasia, scarring and thrombosis, and a reduction in the number of intra-acinar arteries, as well as the arterial-to-alveolar ratio. These vascular changes result in eventual obliteration of the pulmonary vascular bed with elevation in pulmonary vascular resistance and extreme sensitivity to vasoconstricting stimuli. If uncorrected, these children will suffer from morbidity from cyanosis and myocardial failure (12,34,49).Multiple studies have shown that increased pulmonary blood flow and/or pressure affect endothelial cell functions within the alveolar space. Grigg et al. (22) found elevated levels of endothelin-1 (ET-1) in bronchoalveolar lavage in children with congenital heart disease with increased pulmonary blood flow. Ishikawa et al. (36) found elevated plasma ET-1 levels in children with ventricular septal defects who had both volume and pressure overload to the pulmonary circulation but not in children with atrial septal defects who had only volume overload. In cultured human vascular endothelial cells, shear stress stimulated the synthesis of mRNA for platelet-derived growth factors-A and -B (48), tissue plasminogen activator (20), and intercellular adhesion molecule-1 (46).Recently, increased pulmonary blood flow and/or pressure has also been shown to affect pulmonary epithelial cell functions. Wang et al. (59) showed that, in an isolated, constantly inflated, blood-perfused rat lung, increased left atrial pressure increa...

Nitric oxide decreases surfactant protein gene expression in primary cultures of type II pneumocytes

“…Bhandari et al (4) found, in freshly isolated fetal type II cells, that exposure to S-nitroso-N-acetylpenicillamine (SNAP) and hyperoxia decreased surfactant protein mRNA levels. Ayad and Wong (2) In addition, in a lamb model of CHD with increased pulmonary blood flow and pressure, the interaction between NO and endothelin (ET)-1 signaling was found to mediate the dynamic changes in vascular tone following acute changes in fetal pulmonary blood flow (5-6, 47) and was also associated with a gradual decrease in surfactant protein gene expression (23,37).Although the effect of NO on surfactant has been studied previously, the model systems used whether in vivo or in vitro have made the interpretation of the effect of NO on surfactant protein gene expression difficult. In whole lung or mixed cell…”

Surfactant phospholipids and proteins are increased in fetal sheep with pulmonary hypertension secondary to fetal systemic arteriovenous fistula

“…With regard to mechanisms possibly involved in surfactant changes in the present SAVF model, and similar to previous studies (20,29), only assumptions can be proposed at present. Mechanical forces are known to modify alveolar epithelial cell phenotype as well as expression of surfactant proteins in vitro (18,19,21) and in vivo in normal (17,25,30,33) and hypoplastic lungs (8,9).…”

“…To our knowledge, the effects of increased pulmonary blood flow and/or pulmonary hypertension on the surfactant compartment were investigated previously in one model only that consisted in aortopulmonary shunt established at term in lamb fetuses (20,29), the lamb lungs being studied after spontaneous delivery, at 1 mo of life in a first step (20), then during the first postnatal week (29). Whereas no change was found in the first week, at 1 mo the authors reported a decrease in SP-A mRNA content to 61 Ϯ 8% of control value with a consistent decrease of SP-A to 50 Ϯ 12% of age-matched control value, and although SP-B mRNAs were not significantly changed, SP-B was found to be decreased to 74 Ϯ 25% of control value (20).…”

“…First, the fistula in SAVF model has been created at 0.80 gestation, i.e., when alveolar epithelium is not fully mature in terms of surfactant storage, whereas aortopulmonary shunt in the previous studies (20,29) was placed close to term, when lungs were already fully mature. In this model, contrary to our model, lamb lungs therefore did not experience hypertension during the phase of prenatal surfactant storage.…”

“…Using the model of aortopulmonary shunt that is associated with chronic pulmonary high blood flow (34), Gutierrez et al (20) found a decrease in the lung content of two surfactant proteins, SP-A and SP-B, in 4-wk-old lambs, which suggests that alterations in pulmonary blood flow and/or pressure may also influence phenotypic expression of alveolar epithelial cells. More recently, the same group of investigators reported that these changes are not observed during the first week of life (29). However, the surfactant compartment was not thoroughly explored, since the phospholipid moiety was examined during the first week only.…”