Growth hormone (GH) receptor knockout mice reveal actions of GH in lung development

Abstract

The presence of growth hormone (GH) and GH receptors (GHRs) in the lung suggests it is an autocrine/paracrine target site for pulmonary GH action and/or an endocrine site of pituitary GH action. Roles for GH in lung growth or pulmonary function are, however, uncertain. The possibility that pituitary and/or pulmonary GH have physiological roles in lung development has therefore been investigated in GHR knockout (KO or -/-) mice, using a proteomics approach to determine if an absence of GH-signaling affects the proteome of the developing lung. More than 600 proteins were detected by 2-DE in the lungs of control [GHR (+/+)] and GHR (-/-) mice at the end of the alveolarization period (at day 14 postnatally). Of these, 39 differed significantly in protein content at the p>0.05 level [6 were of higher abundance in the GHR (-/-) group, 33 were of lower abundance] and 17 differed at the p>0.02 level [5 of higher abundance in the GHR (-/-) group, 12 of lower abundance] and 7 were definitively identified by MS. Vimentin, a protein involved in cellular proliferation, was reduced in content by approximately 75% in the lungs of the GHR (-/-) mice. Three proteins involved in oxidative protection [SH3 domain-binding glutamic acid-rich-like protein, peroxiredoxin 6 (Prdx6), and isocitrate dehydrogenase 1] were also of lower content in the GHR (-/-) lungs (by approximately 88%, 81% and 70%, respectively). Prdx6 is also involved in lipid and surfactant metabolism, as is apolipoprotein A-IV, the lung content of which was reduced by approximately 73% in these mice. Proteasome 26S ATPase subunit 4, a protein involved in the non-lysosomal degradation of intracellular proteins, and electron flavoprotein alpha subunit , involved in intracellular metabolism, were also reduced in content in the lungs of the GHR (-/-) mice (by approximately 70% and 49%, respectively). These results therefore suggest that these proteins are normally dependent upon GH signaling, and that GH is normally involved in early lung growth, oxidative protection, lipid and energy metabolism and in proteasomal activity. These roles may reflect endocrine actions of pituitary GH and/or local autocrine/paracrine actions of GH produced within the lung.

Spatially-Resolved Proteomics: Rapid Quantitative Analysis of Laser Capture Microdissected Alveolar Tissue Samples

“…The biological functions enriched in cluster 5, which includes proteins higher in abundance at PND7, were all related to actin polymerization and de-polymerization; appearing to indicate cytoskeleton-driven tissue reorganization. Notably, the intermediate filament protein vimentin4546 and the actin de-polymerization protein cofilin-14748 which are often used as Epithelial-Mesenchymal Transition (EMT) markers are higher at PND7 compared to E16.5 and PND28 (T-test pvalue < 0.01)4849. The functions enriched in the proteins that were higher in abundance postnatally relative to in-utero (cluster 6) include oxidative stress response, likely upregulated as exposure to air with respiration has begun, and immune response related proteins, probably triggered by the exposure of the lungs to microorganisms in the ambient environment after birth or recruitment of bone marrow-derived cells into the lung.…”

Lethal lung hypoplasia and vascular defects in mice with conditionalFoxf1overexpression

“…Interestingly, Sox11 −/− mice exhibit lung hypoplasia and die at birth (Sock et al, 2004). Ghr signaling is involved in early lung growth, oxidative protection, and lipid metabolism in the developing lung (Beyea et al, 2006). These genes could potentially be direct targets of FOXF1 in the embryonic and early postnatal lung.…”

Extrapituitary growth hormone

“…The GH ODN also significantly altered the abundance of 32 other, unidentified proteins in the lung. Other proteomic changes in the lungs of GHR(-/-) mice [223] may similarly reflect a loss of autocrine or paracrine GH signaling in the lung. Autocrine or paracrine actions of GH within the lung are also indicated by proteomic responses to the specific overexpression of GH within the lung [224].…”