Fetal rat lung epithelium has a functional growth hormone receptor coupled to tyrosine kinase activity and insulin-like growth factor binding protein-2 production

Abstract

Although growth hormone (GH) receptor (GHR) mRNA and protein are present in fetal tissues such as the lung, there is little evidence that GH mediates growth in the fetus. We have identified functional responses to GH in fetal rat lung epithelia and suggest a possible role for GHR in the developing lung. GHR mRNA in lung extracts was high before birth at day 16 of gestation (16f), decreased to low levels at day 22f but increased again after birth. At day 20f GHR mRNA levels were higher in lung than in liver, whereas growth hormone binding protein mRNA levels were approximately equal in lung and liver. Stimulation of primary cell cultures of day 19f lung epithelia with GH caused increased tyrosine phosphorylation in specific proteins, demonstrating functional GHR. Lung fibroblasts isolated at the same time did not respond to GH. Ligand and Northern blot analysis of the epithelial cultures revealed that GH stimulation increased insulin-like growth factor binding protein-2 (IGFBP-2) activity and mRNA. These experiments demonstrate the functional activity of GHR, specifically in fetal lung epithelium. We suggest that one role for GH in vivo may be indirectly to modify insulin-like growth factor activity in the developing fetal lung by increasing IGFBP-2.

Growth hormone expression in the perinatal and postnatal rat lung

“…Immunocytochemistry and in situ hybridization (ISH) have also localized GHR and GHR mRNA within fetal rat lung epithelial cells (Garcia-Aragon et al, 1992;Edmondson et al, 1995) and GHRs have also been identified by Western blotting in fetal (Walker et al, 1992) and adult (Frick et al, 1998) rat lungs. Batchelor et al (1998) also found that the GHR mRNA was present in the rat lung from ED16 -ED21, corresponding to part of the pseudoglandular, the canalicular, and part of the saccular stages of rat lung development, and found that it was 50% more abundant than in the liver, which is a recognized GH target site (Baumbach et al, 1989). Moreover, these authors showed that GH stimulation of the receptor-induced tyrosine kinase activity, indicating that the fetal rat lung GHR is functional.…”

“…Whereas roles for lung GH in lung development are currently unknown, it may participate in its vascularization, as GH stimulates angiogenesis in other tissues (Struman et al, 1999;Corbacho et al, 2002). It may also participate in cellular differentiation (Sanders and Harvey, 2004) or regulate immune function within the lung (Batchelor et al, 1998;Waters et al, 1999;Allen et al, 2000).…”

“…The possibility that the lung is a target site for GH action is also indicated by the GH-induced production of superoxide by alveolar macrophages (Edwards et al, 1992), the GH-induced increase in circulating lung neutrophil activation during sepsis, and the accompanying increase in microvascular injury (Liu et al, 2002a). Exogenous GH also induces NFB activation in the lung (Liu et al, 2002b), increases phosphorylase A activity (Jost et al, 1979), and stimulates the tyrosine phosphorylation of specific proteins in lung epithelial cells (Batchelor et al, 1998). The GH receptor (GHR) gene is also expressed in pulmonary tissues (e.g., Tiong et al, 1989;Garcia-Aragon et al, 1992;Batchelor et al, 1998).…”

“…Exogenous GH also induces NFB activation in the lung (Liu et al, 2002b), increases phosphorylase A activity (Jost et al, 1979), and stimulates the tyrosine phosphorylation of specific proteins in lung epithelial cells (Batchelor et al, 1998). The GH receptor (GHR) gene is also expressed in pulmonary tissues (e.g., Tiong et al, 1989;Garcia-Aragon et al, 1992;Batchelor et al, 1998). Pituitary GH, thus, is likely to be an endocrine regulator of lung growth and function in juvenile development and in adulthood.…”

Growth hormone (GH) action in the developing lung: Changes in lung proteins after adenoviral GH overexpression

“…GH receptors (GHRs) are present in the lung (Tiong et al, 1989;Garcia-Aragon et al, 1992;Batchelor et al, 1998) and exogenous GH induces the production of superoxide (Edwards et al, 1992), increases the activity of NFB (Liu et al, 2002) and phosphorylase A (Jost et al, 1979), and stimulates the tyrosine phosphorylation of specific, but unidentified, proteins in lung epithelial cells (Batchelor et al, 1998). Pathological changes in pituitary GH secretion also result in changes in lung function, because large lungs (Bartlett, 1971), upper airflow obstruction (Trotman-Dick-only be responsive to GH in peripheral circulation, but to GH produced locally as well.…”