Changes in Expression of Platelet-Derived Growth Factor and Its Receptors in the Lungs of Newborn Rats Exposed to Air or 60% O2

Buch, Shilpa; Han, Rui; Cabacungan, Judy; Wang, Jinxia; Yuan, Shi-Zeng; Belcastro, Rosetta; Deimling, Julie; Jankov, Robert P.; Luo, Xiaoping; Lye, Stephen J.; Post, Martin; Tanswell, A. Keith

doi:10.1203/00006450-200010000-00003

Cited by 53 publications

(58 citation statements)

References 36 publications

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“…Because lung pdgf-r␣ mRNA declines during P1 through P14 (5), whereas PDGF-AA mRNA remains constant (6), the decline in pdgf-r␣ expressing LF (pdgfr␣-LF) does not result from diminished PDGF-AA ligand. However, the abundance of pdgfr␣-LF is influenced by receptor activity.…”

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confidence: 99%

Fibroblasts Expressing PDGF-Receptor-Alpha Diminish During Alveolar Septal Thinning in Mice

McGowan

McCoy

2011

Pediatr Res

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In mice, secondary alveolar septal formation primarily occurs during a brief postnatal period and is accompanied by transient expansion of the interstitial lung fibroblast (LF) population. PDGF-A, which solely signals through PDGF-receptor-alpha (PDGF-R␣), is required for expansion, but the receptor's relevant downstream targets remain incompletely defined. We have evaluated the proliferation, apoptosis, and differential response to the selective protein tyrosine kinase inhibitor, imatinib, by pdgfr␣-expressing LF (pdgfr␣-LF) and compared them with their nonexpressing LF counterparts. Our objective was to determine whether diminished signaling through PDGF-R␣-mediated pathways regulates the decline in myofibroblasts, which accompanies septal thinning and ensures more efficient alveolar gas exchange. Using quantitative stereology and flow cytometry at postnatal d 12 and 14, we observed that imatinib caused a selective suppression of proliferation and an increase in apoptosis. The number of the alpha smooth muscle actin (␣SMA) producing pdgfr␣-LF was also reduced. Using cultures of neonatal mouse LF, we showed that imatinib did not suppress PDGF-R␣ gene expression but reduced PDGF-A-mediated Akt phosphorylation, potentially explaining the increase in apoptosis. Our findings are relevant to bronchopulmonary dysplasia in which positive pressure ventilation interferes with myofibroblast depletion, septal thinning, and capillary maturation.

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confidence: 99%

Fibroblasts Expressing PDGF-Receptor-Alpha Diminish During Alveolar Septal Thinning in Mice

McGowan

McCoy

2011

Pediatr Res

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“…Recovery of these animals in room air, following 95% O 2 exposure, is essentially complete by 4 wk (10,11). By contrast, animals exposed to 60% O 2 for 14 d, like infants with BPD, show a marked heterogeneity of response to injury in different lung regions (12). However, recovery of these animals is hard to assess in the short term.…”

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confidence: 99%

Lgl1 Is Suppressed in Oxygen Toxicity Animal Models of Bronchopulmonary Dysplasia and Normalizes During Recovery in Air

et al. 2006

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Bronchopulmonary dysplasia (BPD), a major cause of morbidity in premature infants, is characterized by arrest of lung growth and inhibited alveologenesis. We had earlier cloned lategestation lung 1 (LGL1), a glucocorticoid (GC)-induced, developmentally regulated gene in lung mesenchyme, and showed that reduced levels of late-gestation lung 1 protein (lgl1) inhibit lung branching. Maximal fetal expression of LGL1 is concordant with the onset of alveolar septation, suggesting an additional role for lgl1 in alveologenesis. At postnatal d 7, during the period of maximal septation in postnatal rat lung, lgl1 concentrates at the tips of budding secondary alveolar septa. We studied two models of impaired postnatal alveologenesis generated by exposure of newborn rats to 60% O 2 for 2 wk or 95% O 2 for 1 wk. A profound decrease of lgl1 expression with oxygen exposure was observed in both animal models. Animals exposed to 95% O 2 for 1 wk recovered in air over a 3-wk period, associated with normalization of lgl1 levels. Changes in lung levels of ␣-actin (a marker of myofibroblast differentiation associated with alveologenesis) and the mesenchymal marker vimentin were significant but less marked. Our findings support a role for lgl1 in postnatal lung development. We speculate that deficiency of lgl1 contributes to the arrested alveolar partitioning observed in BPD and that recovery is associated with normalization of lgl1 levels.

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“…Exposure of these newborn rats to 60% O 2 significantly increased the mRNA for PDGF-B and that of the ␣ and ␤ receptor but not PDGF-A. PDGF-A and -B and the ␣ receptor immunoreactivity were reduced and delayed in hyperoxia, consistent with overall inhibition of lung growth (39). Evidence of a role for PDGF-B in lung growth was shown by a reduction in lung DNA synthesis after treatment with PDGF-BB neutralizing antibodies.…”

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confidence: 70%

“…Similarly, PDGF-A and the ␣ receptor immunoreactivity varied from 0 to 14 d, with the intensity and distribution changing as various tissue elements, e.g. epithelium and microvasculature matured and underwent growth and differentiation (39). Exposure of these newborn rats to 60% O 2 significantly increased the mRNA for PDGF-B and that of the ␣ and ␤ receptor but not PDGF-A.…”

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confidence: 93%

Responses of Pulmonary Platelet-Derived Growth Factor Peptides and Receptors to Hyperoxia and Nitric Oxide in Piglet Lungs

et al. 2005

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Changes in Expression of Platelet-Derived Growth Factor and Its Receptors in the Lungs of Newborn Rats Exposed to Air or 60% O2

Cited by 53 publications

References 36 publications

Fibroblasts Expressing PDGF-Receptor-Alpha Diminish During Alveolar Septal Thinning in Mice

Fibroblasts Expressing PDGF-Receptor-Alpha Diminish During Alveolar Septal Thinning in Mice

Lgl1 Is Suppressed in Oxygen Toxicity Animal Models of Bronchopulmonary Dysplasia and Normalizes During Recovery in Air

Responses of Pulmonary Platelet-Derived Growth Factor Peptides and Receptors to Hyperoxia and Nitric Oxide in Piglet Lungs

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