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Martin Post

Publications and source records attributed to Martin Post.

43 records · Page 3Linked to original sources
PubMed2003

Down-regulation of sonic hedgehog expression in pulmonary hypoplasia is associated with congenital diaphragmatic hernia.

The pathogenesis of pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH) is unknown. The sonic hedgehog (Shh) cascade is crucial for the patterning of the early respiratory system in mice. To establish whether Shh plays a role in the pathogenesis of lung hypoplasia in CDH, we investigated the gestation-specific expression of Shh in normal rat and human lungs using in situ hybridization and immunohistochemistry. The expression pattern was compared with that of age-matched samples of hypoplastic lungs associated with CDH in humans and in the 2,4-dichlorophenyl-p-nitrophenylether (nitrofen) rat model. Our results showed that in normal controls the expression of Shh increased with advancing gestation, peaked in the late pseudoglandular stage, and declined thereafter. The expression of Shh is initially down-regulated in pulmonary hypoplasia associated with CDH and peaks instead during the late canalicular stage. These data indicate that maximal expression of Shh occurs when respiratory bronchioles develop and thinning of the interstitium takes place, suggesting that Shh may play a role in these processes. Furthermore, we observed that Shh inhibited fetal lung fibroblast proliferation in vitro. Therefore, it is tempting to speculate that alterations in Shh expression may affect these developmental processes, thereby contributing to the pulmonary abnormality in CDH.

Animals↗
PubMed2003

Genetic control of lung development.

Lung organogenesis is a developmental process that starts in human 4-5 weeks after conception and continues during the first years of life. It can be subdivided in six different stages: embryonic, pseudoglandular, canalicular, saccular and alveolar stage and stage of vascular maturation. In each of these periods, multiple molecules like transcription factors, growth factors and other signaling molecules and their respective receptors control and coordinate the course of events by a distinct expression and activity over space and time. Epithelial-mesenchymal interactions, physiological mechanical forces as well as humoral factors modulate some of these expression patterns. Although numerous key players and their mode of action have been discovered, many wait to be unveiled. Herein, we will summarize the current concepts of lung development with special consideration of the genetic control of lung genesis, growth and maturation.

Cell Differentiation↗
PubMed2003

Insulin-like growth factor-I receptor-mediated vasculogenesis/angiogenesis in human lung development.

The structural and functional development of the pulmonary system is dependent upon appropriate early vascularization of the embryonic lung. Our previous in vitro studies in a rat model indicated that insulin-like growth factor-I (IGF-I) is a potent angiogenic agent for fetal lung endothelial cells. To assess its role on human vascular lung development, we first examined the expression of IGF-I/II and IGF receptor type I (IGF-IR) in human embryonic and fetal lung tissues at 4-12 wk of gestation. Immunohistochemical and in situ hybridization studies revealed the presence of IGF-I/II-IGF-IR ligands and mRNA transcripts in embryonic lungs as early as 4 wk gestation. Immunotargeting using an anti-IGF-IR neutralizing antibody on human fetal lung explants demonstrated a significant blockade of IGF-IR signaling. Inactivation of IGF-IR resulted in a loss of endothelial cells, accompanied by dramatic changes in fetal lung explant morphology. Terminal transferase dUTP end-labeling assay and TEM studies of anti-IGF-IR-treated lungs demonstrated numerous apoptotic mesenchymal cells. Rat embryonic lung explant studies further validated the importance of the IGF-IGF-IR system for lung vascular development. These data provide the first demonstration of IGF-I/II expression in the human lung in early gestation and indicate that the IGF family of growth factors, acting through the IGF-IR, is required as a survival factor during normal human lung vascularization.

Animals↗
PubMed2002

Platelet-derived growth factor-BB-mediated glycosaminoglycan synthesis is transduced through Akt.

Previously we have demonstrated that the phosphoinositide 3-kinase (PI-3K) signal-transduction pathway mediates platelet-derived growth factor (PDGF)-BB-induced glycosaminoglycan (GAG) synthesis in fetal lung fibroblasts. In the present study we further investigated the signal-transduction pathway(s) that results in PDGF-BB-induced GAG synthesis. Over-expression of a soluble PDGF beta-receptor as well as a mutated form of the beta-receptor, unable to bind PI-3K, diminished GAG synthesis in fetal lung fibroblasts subsequent to PDGF-BB stimulation. The PI-3K inhibitor wortmannin blocked PDGF-BB-induced Akt activity as well as significantly diminishing PDGF-BB-mediated GAG synthesis. Expression of dominant-negative PI-3K also abrogated Akt activity and GAG synthesis. Furthermore, expression of dominant-negative Akt abrogated endogenous Akt activity, Rab3D phosphorylation and GAG synthesis, whereas expression of constitutively activated Akt stimulated Rab3D phosphorylation and GAG synthesis in the absence of PDGF-BB. Over-expression of wild-type PTEN (phosphatase and tensin homologue deleted in chromosome 10) inhibited Akt activity and concomitantly attenuated GAG synthesis in fibroblasts stimulated with PDGF-BB. These data suggest that Akt is an integral protein involved in PDGF-BB-mediated GAG regulation in fetal lung fibroblasts.

Androstadienes↗
PubMed2002

Cell cycle regulation of pulmonary phosphatidylcholine synthesis.

Pulmonary surfactant phosphatidylcholine (PC) formation increases as alveolar type II cells mature and arrest in G0/G1 state of the cell cycle at late fetal gestation. To determine whether this G0/G1 arrest is responsible for the increase in PC synthesis, we investigated the rates of PC synthesis and the activity, phosphorylation, intracellular distribution, synthesis, and degradation of a key enzyme of PC synthesis, cytidine triphosphate (CTP):phosphocholine cytidylyltransferase (CCTalpha). In synchronized mouse lung epithelial (MLE)-15 cells, PC production and CCTalpha activity peaked at G0/G1, declined during transition to G1/S, and remained low during S and G2/M. The changes in CCTalpha activity were not due to alterations in CCTalpha gene and protein expression. CCTalpha protein degradation also did not change during the cell cycle. Indirect immunofluorescence and immunogold electron microscopy revealed that CCTalpha localized to the cytoplasmic compartment and that its cytosolic localization did not change with the cell cycle. Although immunoblotting suggested no major redistribution of CCTalpha mass from cytosol to endoplasmic reticulum, activity measurements revealed that the ratio of particulate/soluble CCTalpha activity was cell cycle-dependent. The particulate/soluble ratio peaked at G0/G1 and declined with cell-cycle progression. Furthermore, the decrease in CCTalpha activity during exit from G0/G1 was associated with an increase in CCTalpha phosphorylation. These data suggest that the cell-cycle changes in PC synthesis are likely not due to alterations in CCTalpha expression and degradation but are primarily a consequence of changes in CCTalpha activity, phosphorylation, and membrane affinity.

Animals↗
PubMed2002

A role for platelet-derived growth factor-BB in rat postpneumonectomy compensatory lung growth.

Unilateral pneumonectomy leads to compensatory growth in the residual lung, the mediators of which are largely unknown. We hypothesized, based on its other known roles in lung cell growth, that platelet-derived growth factor (PDGF)-BB would be an essential mediator of postpneumonectomy compensatory lung growth. Left-sided pneumonectomies were performed on 21-d-old rats, for comparison with sham-operated or unoperated control animals. Body weights were not different between groups. Right lung weights and DNA content were significantly increased (p < 0.05), compared with controls, by 10 d after pneumonectomy. The rate of DNA synthesis was maximal on d 5 postpneumonectomy. Total right lung PDGF-B mRNA and PDGF-BB protein increased after pneumonectomy, but were apparently tightly regulated, relative to total right lung beta-actin mRNA and protein content, respectively. However, PDGF-BB expression after pneumonectomy was apparently not purely constitutive, in that daily i.p. injections of a truncated soluble PDGF beta-receptor both reduced activation of the native PDGF beta-receptor, and attenuated increased lung DNA synthesis on d 3 after pneumonectomy. These findings are consistent with a critical role for PDGF-BB in postpneumonectomy lung growth.

Adaptation, Physiological↗