Abstract
The association between lung injury and thrombocytopenia was investigated by comparing the megakaryocyte and platelet counts, and platelet activation using P-selectin as a marker, between the prepulmonary (right atrial) and postpulmonary (left atrial) blood in adult and neonatal (preterm and term) rats with and without hyperoxic lung injury. In the healthy controls, the postpulmonary blood had lower megakaryocyte count (prepulmonary versus postpulmonary: Preterm: 8.7[0.6]versus 3.9[0.3] per ml, p < 0.001; Term: 8.7[1.1]versus 2.6[0.4] per ml, p < 0.001; Adult: median [interquartile ranges]: 2.5[1.0, 5.0]versus 1.0[0, 3.0] per ml, p < 0.001), higher platelet count (prepulmonary versus postpulmonary: Preterm: 491.2[11.1] × 109/L versus 595.1[10.2] × 109/L, p < 0.001; Term: 472.5[19.9] × 109/L versus 579.3[26.2] × 109/L, p < 0.001; Adult: 513.9[31.5] × 109/L versus 664.7[28.8] × 109/L, p < 0.001), but similar P-selectin expression. In contrast, the lung-damaged animals did not show any such differences in either megakaryocyte or platelet count, but P-selectin expression was greater in the postpulmonary blood (prepulmonary versus postpulmonary: Preterm: 38.7[3.9]versus 56.4[4.9]% platelets, p = 0.02; Term: 40.9[2.0]versus 54.0[4.2]% platelets, p = 0.002; Adults: 30.0[3.6]versus 49.1[4.7]% platelets, p = 0.003). Peripheral platelet and intra-pulmonary megakaryocyte counts in the lung-damaged rats were significantly lower than those in their respective controls. Intra-pulmonary thrombi or platelet aggregation were detected in the lung-damaged rats but not in the controls. These findings showed that hyperoxic lung damage reduced circulating platelets through (1) failure of the lungs to retain and fragment megakaryocytes to release platelets, and (2) platelet activation leading to platelet aggregation, thrombi formation and platelet consumption. The magnitude of platelet reduction was physiologically significant, as demonstrated by higher counts of megakaryocyte colony forming units in the bone marrow culture of the animals in the hyperoxia group when compared with the controls.
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Abbreviations
- AchE:
-
acetylcholine esterase
- CFU-MK:
-
colony forming unit of megakaryocyte
- FITC:
-
fluorescin isothiocyanate
- HPF:
-
high power field
- IgG:
-
IgG
- MK:
-
megakaryocyte
- PE:
-
phycoerythrin
References
Burrows RF, Kelton JG 1990 Thrombocytopenia at delivery: a prospective survey of 6715 deliveries. Am J Obstet Gynecol 162: 731–734
Burrows RF, Kelton JG 1988 Incidentally detected thrombocytopenia in healthy mothers and their infants. N Engl J Med 319: 142–145
Castle V, Andrew M, Kelton J, Giron D, Johnston M, Carter C 1986 Frequency and mechanism of neonatal thrombocytopenia. J Pediatr 108S( Pt 1): 749–755
Murray NA, Roberts IA 1996 Circulating megakaryocytes and their progenitors in early thrombocytopenia in preterm neonates. Pediatr Res 40: 112–119
Mehta P, Vasa R, Neumann L, Karpatkin M 1980 Thrombocytopenia in the high-risk infant. J Pediatr 97: 791–794
Castle V, Coates G, Kelton JG, Andrew M 1987 111In-oxine platelet survivals in thrombocytopenic infants. Blood 70: 652–656
Zipursky A, Palko J, Milner R, Akenzua GI 1976 The hematology of bacterial infections in premature infants. Pediatrics 57: 839–853
Ballin A, Koren G, Kohelet D, Burger R, Greenwald M, Bryan AC, Zipursky A 1987 Reduction of platelet counts induced by mechanical ventilation in newborn infants. J Pediatr 111: 445–449
Kohelet D, Perlman M, Hanna G, Ballin A 1990 Reduced platelet counts in neonatal respiratory distress syndrome. Biol Neonate 57: 334–342
Schmidt B, Vegh P, Weitz J, Johnston M, Caco C, Roberts R 1992 Thrombin/antithrombin III complex formation in the neonatal respiratory distress syndrome. Am Rev Respir Dis 145( Pt 1): 767–770
Brus F, van Oeveren W, Okken A, Oetomo SB 1997 Number and activation of circulating polymorphonuclear leukocytes and platelets are associated with neonatal respiratory distress syndrome severity. Pediatrics 99: 672–680
Steele P, Ellis JH, Weily HS, Genton E 1977 Platelet survival time in patients with hypoxemia and pulmonary hypertension. Circulation 55: 660–661
Zucker-Franklin D, Philipp CS 2000 Platelet production in the pulmonary capillary bed: new ultrastructural evidence for an old concept. Am J Pathol 157: 69–74
Levine RF, Eldor A, Shoff PK, Kirwin S, Tenza D 1993 Circulating megakaryocytes: delivery of large numbers of intact, mature megakaryocytes to the lungs. Eur J Haematol 51: 233–246
Graeve JLA, de Alarcon PA 1989 Megakaryocytopoiesis in the human fetus. Arch Dis Child 64: 481–484
Woods MJ, Landon CR, Wagner BE, Greaves M, Trowbridge EA 1992 Isolation of circulating megakaryocytes in man. Med Lab Sci 49: 252–258
Martin JF, Slater DN, Trowbridge EA 1983 Abnormal intrapulmonary platelet production: a possible cause of vascular and lung disease. Lancet 1( 8328): 793–796
Pedersen NT 1971 Circulating megakaryocytes in blood from the inferior vena cava in adult rats. Scand J Haematol 8: 223–230
Pedersen NT 1974 The pulmonary vessels as a filter for circulating megakaryocytes in rats. Scand J Haematol 13: 225–231
Aschoff L 1893 Üeber capilläre Embolie von riesenkernhaltigen Zellen. Virchows Arch Pathol Anat Physiol Klin Med 134: 11–26
Howell WH, Donohue DD 1937 The production of blood platelets in the lungs. J Exp Med 65: 171–204
Kaufman RM, Airo R, Pollack S, Crosby WH 1965 Circulating megakaryocytes and platelets release in the lung. Blood 26: 720–731
Kallinikos-Maniakas A 1969 Megakaryocytes and platelets in central venous and arterial blood. Acta Haematol 42: 330–335
Pedersen NT 1978 Occurrence of megakaryocytes in various vessels and their retention in the pulmonary capillaries in man. Scand J Haematol 21: 369–375
Wilde NT, Burgess R, Keenan DJ, Lucas GS 1997 The effect of cardiopulmonary bypass on circulating megakaryocytes. Br J Haematol 98: 322–327
Trowbridge EA, Martin JF, Slater DN 1982 Evidence for a theory of physical fragmentation of megakaryocytes, implying that all platelets are produced in the pulmonary circulation. Thromb Res 28: 461–475
Tanswell AK, Wong L, Possmayer F, Freeman BA 1989 The preterm rat: a model for studies of acute and chronic neonatal lung disease. Pediatr Res 25: 525–529
Deng H, Mason SN, Auten RL 2000 Lung inflammation in hyperoxia can be prevented by antichemokine treatment in newborn rats. Am J Respir Crit Care Med 162: 2316–2323
Appleby CJ, Towner RA 2001 Magnetic resonance imaging of pulmonary damage in the term and premature rat neonate exposed to hyperoxia. Pediatr Res 50: 502–507
Iwata M, Takagi K, Satake T, Sugiyama S, Ozawa T 1986 Mechanism of oxygen toxicity in rat lungs. Lung 164: 93–106
Chen Y, Martinez MA, Frank L 1997 Prenatal dexamethasone administration to premature rats exposed to prolonged hyperoxia: a new rat model of pulmonary fibrosis (bronchopulmonary dysplasia). J Pediatr 130: 409–416
Yang M, Chesterman CN, Chong BH 1995 Recombinant PDGF enhances megakaryocytopoiesis in vitro. Br J Haematol 91: 285–289
Woods MJ, Greaves M, Smith GH, Trowbridge EA 1993 The fate of circulating megakaryocytes during cardiopulmonary bypass. J Thorac Cardiovasc Surg 106: 658–663
Shattil SJ, Cunningham M, Hoxie JA 1987 Detection of activated platelets in whole blood using activation- dependent monoclonal antibodies and flow cytometry. Blood 70: 307–315
Han ZC, Briere J, Abgrall JF, Sensebe L, Nedellec G, Parent D, Guern G 1987 Spontaneous formation of megakaryocyte progenitors (CFU-MK) in primary thrombocythaemia. Acta Haematol 78: 51–53
Berman CL, Yeo EL, Wencel-Drake JD, Furie BC, Ginsberg MH, Furie B 1986 A platelet alpha granule membrane protein that is associated with the plasma membrane after activation. Characterization and subcellular localization of platelet activation-dependent granule-external membrane protein. J Clin Invest 78: 130–137
Doyle DJ, Chesterman CN, Cade JF, McGready JR, Rennie GC, Morgan FJ 1980 Plasma concentrations of platelet-specific proteins correlated with platelet survival. Blood 55: 82–84
Barazzone C, Tacchini-Cottier F, Vesin C, Rochat AF, Piguet PF 1996 Hyperoxia induces platelet activation and lung sequestration: an event dependent on tumor necrosis factor-alpha and CD11a. Am J Respir Cell Mol Biol 15: 107–114
Baumgartner HR, Hosang M 1988 Platelets, platelet-derived growth factor and arteriosclerosis. Experientia 44: 109–112
Chignier E, Parise M, McGregor L, Delabre C, Faucompret S, McGregor J 1994 A P-selectin/CD62P monoclonal antibody (LYP-20), in tandem with flow cytometry, detects in vivo activated circulating rat platelets in severe vascular trauma. Thromb Haemost 72: 745–749
George JN, Pickett EB, Saucerman S, McEver RP, Kunicki TJ, Kieffer N, Newman PJ 1986 Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects, and observations in patients during adult respiratory distress syndrome and cardiac surgery. J Clin Invest 78: 340–348
Welty SE, Rivera JL, Elliston JF, Smith CV, Zeb T, Ballantyne CM, Montgomery CA, Hansen TN 1993 Increases in lung tissue expression of intercellular adhesion molecule- 1 are associated with hyperoxic lung injury and inflammation in mice. Am J Respir Cell Mol Biol 9: 393–400
Jensen JC, Pogrebniak HW, Pass HI, Buresh C, Merino MJ, Kauffman D, Venzon D, Langstein HN, Norton JA 1992 Role of tumor necrosis factor in oxygen toxicity. J Appl Physiol 72: 1902–1907
Dore M 1998 Platelet-leukocyte interactions. Am Heart J 135( Pt 2 Suppl): S146–S151
Kaushansky K 1995 Thrombopoietin: the primary regulator of megakaryocyte and platelet production. Thromb Haemost 74: 521–525
Ishibashi T, Kimura H, Shikama Y, Uchida T, Kariyone S, Hirano T, Kishimoto T, Takatsuki F, Akiyama Y 1989 Interleukin-6 is a potent thrombopoietic factor in vivo in mice. Blood 74: 1241–1244
Ishibashi T, Kimura H, Uchida T, Kariyone S, Friese P, Burstein SA 1989 Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA 86: 5953–5957
Brandt E, Ernst M, Loppnow H, Flad HD 1989 Characterization of a platelet derived factor modulating phagocyte functions and cooperating with interleukin 1. Lymphokine Res 8: 281–287
Yang M, Li K, Chui CM, Yuen PM, Chan PK, Chuen CK, Li CK, Fok TF 2000 Expression of interleukin (IL) 1 type I and type II receptors in megakaryocytic cells and enhancing effects of IL-1beta on megakaryocytopoiesis and NF-E2 expression. Br J Haematol 111: 371–380
Carrington PA, Hill RJ, Stenberg PE, Levin J, Corash L, Schreurs J, Baker G, Levin FC 1991 Multiple in vivo effects of interleukin-3 and interleukin-6 on murine megakaryocytopoiesis. Blood 77: 34–41
Chang M, Suen Y, Meng G, Buzby JS, Bussel J, Shen V, van de V, Cairo MS 1996 Differential mechanisms in the regulation of endogenous levels of thrombopoietin and interleukin-11 during thrombocytopenia: insight into the regulation of platelet production. Blood 88: 3354–3362
Williams N, Bertoncello I, Jackson H, Arnold J, Kavnoudias H 1992 The role of interleukin 6 in megakaryocyte formation, megakaryocyte development and platelet production. Ciba Found Symp 167: 160–170
Long MW, Henry RL 1979 Thrombocytosis-induced suppression of small acetylcholinesterase-positive cells in bone marrow of rats. Blood 54: 1338
Acknowledgements
We would like to thank Mr. Eric Wong, statistician, Center of Clinical Trial and Epidemiologic Research, Medical Faculty, The Chinese University of Hong Kong for his statistical assistance, and Mr. Raymond Wong, medical technologist, The Department of Paediatrics, The Chinese University of Hong Kong for his assistance in the assay of P-selectin expression.
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This study was supported by an Earmarked Grant of the Research Grant Council, Hong Kong.
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Yang, J., Yang, M., Xu, F. et al. Effects of Oxygen-Induced Lung Damage on Megakaryocytopoiesis and Platelet Homeostasis in a Rat Model. Pediatr Res 54, 344–352 (2003). https://doi.org/10.1203/01.PDR.0000079186.86219.29
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DOI: https://doi.org/10.1203/01.PDR.0000079186.86219.29
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