Abstract
The peptides platelet-derived growth factor-A (PDGF-A) and especially -B have important roles in lung development. The effect of hyperoxic exposure with and without inhaled nitric oxide (iNO) on lung expression of PDGF and its receptors is unknown. We hypothesized that hyperoxia exposure would suppress mRNA expression and protein production of these ligands and their receptors. The addition of iNO to hyperoxia may further aggravate the effects of hyperoxia. Thirteen-day-old piglets were randomized to breathe 1) room air (RA); 2) 0.96 fraction of inspired oxygen (O2), or 3) 0.96 fraction of inspired oxygen plus 50 ppm of NO (O2 + NO), for 5 d. Lungs were preserved for mRNA, Western immunoblot, and immunohistochemical analyses for PDGF-A and -B and their receptors PDGFR-α and -β. PDGF-B mRNA expression was greater than that of PDGF-A or PDGFR-α and -β in RA piglet lungs (p < 0.05). Hyperoxia with or without iNO reduced lung PDGF-B mRNA and protein expression relative to the RA group lungs (p < 0.01). PDGF-B immunostain intensity was significantly increased in the alveolar macrophages, which were present in greater numbers in the hyperoxia-exposed piglet lungs, with or without NO (p < 0.01). PDGFR-β immunostaining was significantly increased in airway epithelial cells in O2- and O2 + NO–exposed piglets. PDGF-A and PDGFR-α immunostain intensity and distribution pattern were unchanged relative to the RA group. Sublethal hyperoxia decreases PDGF-B mRNA and protein expression but not PDGF-A or their receptors in piglet lungs. iNO neither aggravates nor ameliorates this effect.
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Abbreviations
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
- iNO:
-
inhaled nitric oxide
- NO:
-
nitric oxide
- PDGF:
-
platelet-derived growth factor
References
Heldin CH, Westermark B 1999 Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79: 1283–1316
Ostman A, Heldin CH 2001 Involvement of platelet-derived growth factor in disease: development of specific antagonists. Adv Cancer Res 80: 1–38
Betsholtz C, Karlsson L, Lindahl P 2001 Developmental roles of platelet-derived growth factors. Bioessays 23: 494–507
Lindahl P, Bostrom H, Karlsson L, Hellstrom M, Kalen M, Betsholtz C 1999 Role of platelet-derived growth factors in angiogenesis and alveogenesis. Curr Top Pathol 93: 27–33
Bostrom H, Willetts K, Pekny M, Leveen P, Lindahl P, Hedstrand H, Pekna M, Hellstrom M, Gebre-Medhin S, Schalling M, Nilsson M, Kurland S, Tornell J, Heath JK, Betsholtz C 1996 PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85: 863–873
Buch S, Jones C, Sweezey N, Tanswell K, Post M 1991 Platelet-derived growth factor and growth-related genes in rat lung. I. Developmental expression. Am J Respir Cell Mol Biol 5: 371–376
Han RN, Liu J, Tanswell AK, Post M 1993 Ontogeny of platelet-derived growth factor receptor in fetal rat lung. Microsc Res Tech 26: 381–388
Souza P, Tanswell AK, Post M 1996 Different roles for PDGF-alpha and -beta receptors in embryonic lung development. Am J Respir Cell Mol Biol 15: 551–562
Fabisiak JP, Evans JN, Kelley J 1989 Increased expression of PDGF-B (c-sis) mRNA in rat lung precedes DNA synthesis and tissue repair during chronic hyperoxia. Am J Respir Cell Mol Biol 1: 181–189
Powell PP, Wang CC, Jones R 1992 Differential regulation of the genes encoding platelet-derived growth factor receptor and its ligand in rat lung during microvascular and alveolar wall remodeling in hyperoxia. Am J Respir Cell Mol Biol 7: 278–285
Han RN, Buch S, Freeman BA, Post M, Tanswell AK 1992 Platelet-derived growth factor and growth-related genes in rat lung. II. Effect of exposure to 85% O2 . Am J Physiol 262: L140–L146
Berg JT, Breen EC, Fu Z, Mathieu-Costello O, West JB 1998 Alveolar hypoxia increases gene expression of extracellular matrix proteins and platelet-derived growth factor-B in lung parenchyma. Am J Respir Crit Care Med 158: 1920–1928
Ekekezie II, Thibeault DW, Zwick DL, Rezaiekhaligh MH, Mabry SM, Morgan RE, Norberg M, Truog WE 2000 Independent and combined effects of prolonged inhaled nitric oxide and oxygen on lung inflammation in newborn piglets. Biol Neonate 77: 37–44
Deuel TF, Senior RM, Huang JS, Griffin GL 1982 Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J Clin Invest 69: 1046–1049
Tzeng DY, Deuel TF, Huang JS, Baehner RL 1985 Platelet-derived growth factor promotes human peripheral monocyte activation. Blood 66: 179–183
Wilson E, Laster SM, Gooding LR, Lambeth JD 1987 Platelet-derived growth factor stimulates phagocytosis and blocks agonist-induced activation of the neutrophil oxidate burst: a possible cellular mechanism to protect against oxygen radical damage. Proc Natl Acad Sci USA 84: 2213–2217
Moore AM, Buch S, Han RN, Freeman BA, Post M, Tanswell AK 1995 Altered expression of type I collagen, TGF-beta 1, and related genes in rat lung exposed to 85% O2 . Am J Physiol 268: L78–L84
Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Mayock DE, Redding GJ, de Lemos RA, Sardesai S, McCurnin DC, Moreland SG, Cutter GR, Abman SH 1997 Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr 131: 55–62
Truog WE 1998 Inhaled nitric oxide: a tenth anniversary observation. Pediatrics 101: 696–697
Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P 2003 Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 349: 2099–2107
Van Meurs KP, Stevenson DK, Ehrenkranz RA, Lemons JA, Poole WK, Perritt R, Higgins RD, Wright LL, Neonatal Research Network 2004 Inhaled nitric oxide for preterm infants with severe respiratory failure. Pediatr Res 55: LB12, 4A
Macrae DJ, Field D, Mercier JC, Moller J, Stiris T, Biban P, Cornick P, Goldman A, Gothberg S, Gustafsson LE, Hammer J, Lonnqvist PA, Sanchez-Luna M, Sedin G, Subhedar N 2004 Inhaled nitric oxide therapy in neonates and children: reaching European consensus. Intensive Care Med 30: 372–380
Gaston B, Drazen JM, Loscalzo J, Stamler JS 1994 The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 149: 538–551
Moncada S, Palmer RM, Higgs EA 1991 Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109–142
Stamler JS, Singel DJ, Loscalzo J 1992 Biochemistry of nitric oxide and its redox-activated forms. Science 258: 1898–1902
Moreno JJ, Pryor WA 1992 Inactivation of α 1-proteinase inhibitor by peroxynitrite. Chem Res Toxicol 5: 425–431
Stricklin GP, Hoidal JR 1992 Oxidant-mediated inactivation of TIMP. Matrix Suppl 1: 325
Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS 1996 Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 98: 2572–2579
Garat C, Jayr C, Eddahibi S, Laffon M, Meignan M, Adnot S 1997 Effects of inhaled nitric oxide or inhibition of endogenous nitric oxide formation on hyperoxic lung injury. Am J Respir Crit Care Med 155: 1957–1964
Nelin LD, Welty SE, Morrisey JF, Gotuaco C, Dawson CA 1998 Nitric oxide increases the survival of rats with a high oxygen exposure. Pediatr Res 43: 727–732
Gutierrez HH, Nieves B, Chumley P, Rivera A, Freeman BA 1996 Nitric oxide regulation of superoxide-dependent lung injury: oxidant-protective actions of endogenously produced and exogenously administered nitric oxide. Free Radic Biol Med 21: 43–52
Kaftan HA, Clark PL, Norberg M, Garg U, Thibeault DW, Truog WE 2003 Endogenous production of nitric oxide in endotoxemic piglets. Biol Neonate 83: 42–48
Issa A, Lappalainen U, Kleinman M, Bry K, Hallman M 1999 Inhaled nitric oxide decreases hyperoxia-induced surfactant abnormality in preterm rabbits. Pediatr Res 45: 247–254
Robbins CG, Davis JM, Merritt TA, Amirkhanian JD, Sahgal N, Morin FC 3rd, Horowitz S 1995 Combined effects of nitric oxide and hyperoxia on surfactant function and pulmonary inflammation. Am J Physiol 269: L545–L550
Truog WE, Castor CA, Sheffield MJ 2003 Neonatal nitric oxide use: predictors of response and financial implications. J Perinatol 23: 128–132
Winkler GC, Cheville NF 1985 Morphometry of postnatal development in the porcine lung. Anat Rec 211: 427–433
Youssef JA, Thibeault DW, Rezaiekhaligh MH, Mabry SM, Norberg MI, Truog WE 1999 Influence of inhaled nitric oxide and hyperoxia on Na,K-ATPase expression and lung edema in newborn piglets. Biol Neonate 75: 199–209
Cho M, Hung TK, Hussain MZ 2001 Hydrogen peroxide stimulates macrophage vascular endothelial growth factor release. Am J Physiol 280: H2357–H2363
Buch S, Han RN, Cabacungan J, Wang J, Yuan S, Belcastro R, Deimling J, Jankov R, Luo X, Lye SJ, Post M, Tanswell AK 2000 Changes in expression of platelet-derived growth factor and its receptors in the lungs of newborn rats exposed to air or 60% O2 . Pediatr Res 48: 423–433
Walsh J, Absher M, Kelley J 1993 Variable expression of platelet-derived growth factor family proteins in acute lung injury. Am J Respir Cell Mol Biol 9: 637–644
Crapo JD, Barry BE, Gehr P, Bachofen M, Weibel ER 1982 Cell number and cell characteristics of the normal human lung. Am Rev Respir Dis 126: 332–337
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Supported, in part, by NIH R-01 HL58125 (W.E.T.) and by K23 HL 04264 (I.I.E.).X.Z. is currently affiliated with the Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160.
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Zhang, X., Reinsvold, P., Thibeault, D. et al. Responses of Pulmonary Platelet-Derived Growth Factor Peptides and Receptors to Hyperoxia and Nitric Oxide in Piglet Lungs. Pediatr Res 57, 523–529 (2005). https://doi.org/10.1203/01.PDR.0000155762.91748.8D
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DOI: https://doi.org/10.1203/01.PDR.0000155762.91748.8D
