Biomedical subjects

Kathryn N Farrow

Publications and source records attributed to Kathryn N Farrow.

3 recordsLinked to original sources

PubMed2005

eNOS function is developmentally regulated: uncoupling of eNOS occurs postnatally.

At birth, the transition to gas breathing requires the function of endothelial vasoactive agents. We investigated the function of endothelial nitric oxide synthase (eNOS) in pulmonary artery (PA) vessels and endothelial cells isolated from fetal and young (4-wk) sheep. We found greater relaxations to the NOS activator A-23187 in 4-wk-old compared with fetal vessels and that the NOS inhibitor nitro-L-arginine blocked relaxations in both groups. Relaxations in 4-wk vessels were not blocked by an inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, but were partially blocked by catalase. We therefore hypothesized that activation of eNOS produced reactive oxygen species in 4-wk but not fetal PA. To address this question, we studied NO and superoxide production by endothelial cells at baseline and following NOS stimulation with A-23187, VEGF, and laminar shear stress. Stimulation of NOS induced phosphorylation at serine 1177, and this event correlated with an increase in NO production in both ages. Upon stimulation of eNOS, fetal PA endothelial cells (PAEC) produced only NO. In contrast 4-wk-old PAEC produced superoxide in addition to NO. Superoxide production was blocked by L-NAME but not by apocynin (an NADPH oxidase inhibitor). L-Arginine increased NO production in both cell types but did not block superoxide production. Heat shock protein 90/eNOS association increased upon stimulation and did not change with developmental age. Cellular levels of total and reduced biopterin were higher in fetal vs. 4-wk cells. Sepiapterin [a tetrahydrobiopterin (BH4) precursor] increased basal and stimulated NO levels and completely blocked superoxide production. We conclude that the normal function of eNOS becomes uncoupled after birth, leading to a developmental adaptation of the pulmonary vascular system to produce oxygen species other than NO. We speculate this may be related to cellular production and/or maintenance of BH4 levels.

Aging↗

PubMed2005

The diseases treated with ECMO: focus on PPHN.

Neonatal extracorporeal support is most often required for neonatal hypoxemic respiratory failure, usually accompanied by persistent pulmonary hypertension of the newborn (PPHN). PPHN is a clinical syndrome that results from the failure of pulmonary vascular transition to extrauterine life. Infants typically present shortly after birth with respiratory distress and cyanosis, but a structurally normal heart. The incidence of PPHN is estimated at 0.2% of live-born term infants. Respiratory failure and hypoxemia in the term newborn result from a heterogeneous group of disorders, and the therapeutic approach and response often depend on the underlying disease. PPHN can largely be thought of as one of three types: (1) the abnormally constricted pulmonary vasculature which is the most common type and includes diagnoses such as meconium aspiration syndrome, respiratory distress syndrome, and sepsis; (2) the structurally abnormal vasculature, which is often termed idiopathic PPHN; or (3) the hypoplastic vasculature such as is seen in congenital diaphragmatic hernia, or alveolar capillary dysplasia, a rare malformation of lung development. The pathophysiology of each type is dependent on the point in gestation when the normal transition to extrauterine life fails. This article will discuss the known pathophysiology in PPHN and new treatment modalities.

Extracorporeal Membrane Oxygenation↗

PubMed2004

Structural and functional analysis of the differential effects of c-Jun and v-Jun on prolactin gene expression.

The protooncogene c-Jun and its oncogenic isoform v-Jun are members of the activator protein 1 family of transcription factors that have been shown to have differential transcriptional effects that are both promoter specific and cell type specific. Previously, we have demonstrated that whereas c-Jun inhibits pituitary-specific rat prolactin (rPRL) promoter activity, expression of v-Jun stimulates the rPRL promoter in GH4 pituitary cells. In this report, we have conducted an extensive structure-function analysis of c-Jun vs. v-Jun to determine which regions of these proteins are responsible for their differential transcriptional effects in this pituitary model system. We show that isoform-specific responses are mediated by complex interactions between the delta-domain, serine 243, and the amino-terminal transcriptional activation domains. Thus, in contrast to previous reports, no single domain is responsible for the differential transcriptional activities of c-Jun and v-Jun. Mutation of c-Jun serine 243 to phenylalanine and replacement of the c-Jun amino terminus with the corresponding region from v-Jun, thereby removing the delta-domain, are necessary and sufficient to confer a functional switch from the c-Jun-inhibitory to the v-Jun-activating phenotype. Thus, we propose that isoform-specific subdomains in c-Jun and v-Jun dictate discrete interactions with distinct protein partners, which underlie the differential Jun-dependent transcriptional responses of the rPRL promoter.

Animals↗