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Am J Pathol. Jan 1998; 152(1): 179–190.
PMCID: PMC1858114

Temporal pattern of accelerated lung growth after tracheal occlusion in the fetal rabbit.


Tracheal occlusion in utero is a potent stimulus of fetal lung growth. We describe the early growth mechanics of fetal lungs and type II pneumocytes after tracheal ligation (TL). Fetal rabbits underwent TL at 24 days gestational age (DGA; late pseudoglandular stage; term = 31 to 33 days) and were sacrificed at time intervals ranging from 1 to 5 days after TL. Lung growth was measured by stereological volumetry and bromodeoxyuridine (BrdU) pulse labeling. Pneumocyte II population kinetics were analyzed using a combination of anti-surfactant protein A and BrdU immunohistochemistry and computer-assisted morphometry. Nonoperated littermates served as controls. TL resulted in dramatically enhanced lung growth (lung weight/body weight was 5.00 +/- 0.81% in TL versus 2.52 +/- 0.13% in controls at 29 DGA; P < 0.001, unpaired Student's t-test). Post-TL lung growth was characterized by a 3-day lag-phase typified by relative stagnation of growth, followed by distension of airspaces, increased cell proliferation, and accelerated architectural and cellular maturation by postligation days 4 and 5. During the proliferation phase, the replicative activity of type II cells was markedly increased (type II cell BrdU labeling index was 10.0 +/- 4.1% in TL versus 1.1 +/- 0.3% for controls at 29 DGA; P < 0.02), but their numerical density decreased (3.0 +/- 0.5 x 10(-3)/microm2 in TL versus 4.5 +/- 0.3 x 10(-3)/microm2 in controls at 29 DGA; P < 0.02), suggesting accelerated terminal differentiation to type I cells. In conclusion, post-TL lung development is characterized by a well defined temporal pattern of lung growth and maturation. The rabbit model lends itself well to study the regulatory mechanisms underlying accelerated fetal lung growth after TL.

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  • Alcorn D, Adamson TM, Lambert TF, Maloney JE, Ritchie BC, Robinson PM. Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung. J Anat. 1977 Jul;123(Pt 3):649–660. [PMC free article] [PubMed]
  • Adzick NS, Harrison MR, Glick PL, Villa RL, Finkbeiner W. Experimental pulmonary hypoplasia and oligohydramnios: relative contributions of lung fluid and fetal breathing movements. J Pediatr Surg. 1984 Dec;19(6):658–665. [PubMed]
  • Hooper SB, Han VK, Harding R. Changes in lung expansion alter pulmonary DNA synthesis and IGF-II gene expression in fetal sheep. Am J Physiol. 1993 Oct;265(4 Pt 1):L403–L409. [PubMed]
  • Papadakis K, Luks FI, De Paepe ME, Piasecki GJ, Wesselhoeft CW., Jr Fetal lung growth after tracheal ligation is not solely a pressure phenomenon. J Pediatr Surg. 1997 Feb;32(2):347–351. [PubMed]
  • DiFiore JW, Fauza DO, Slavin R, Peters CA, Fackler JC, Wilson JM. Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg. 1994 Feb;29(2):248–257. [PubMed]
  • Hedrick MH, Estes JM, Sullivan KM, Bealer JF, Kitterman JA, Flake AW, Adzick NS, Harrison MR. Plug the lung until it grows (PLUG): a new method to treat congenital diaphragmatic hernia in utero. J Pediatr Surg. 1994 May;29(5):612–617. [PubMed]
  • Nardo L, Hooper SB, Harding R. Lung hypoplasia can be reversed by short-term obstruction of the trachea in fetal sheep. Pediatr Res. 1995 Nov;38(5):690–696. [PubMed]
  • Harrison MR, Adzick NS, Flake AW, VanderWall KJ, Bealer JF, Howell LJ, Farrell JA, Filly RA, Rosen MA, Sola A, et al. Correction of congenital diaphragmatic hernia in utero VIII: Response of the hypoplastic lung to tracheal occlusion. J Pediatr Surg. 1996 Oct;31(10):1339–1348. [PubMed]
  • O'Toole SJ, Sharma A, Karamanoukian HL, Holm B, Azizkhan RG, Glick PL. Tracheal ligation does not correct the surfactant deficiency associated with congenital diaphragmatic hernia. J Pediatr Surg. 1996 Apr;31(4):546–550. [PubMed]
  • Bullard KM, Sonne J, Hawgood S, Harrison MR, Adzick NS. Tracheal ligation increases cell proliferation but decreases surfactant protein in fetal murine lungs in vitro. J Pediatr Surg. 1997 Feb;32(2):207–213. [PubMed]
  • Kikkawa Y, Motoyama EK, Gluck L. Study of the lungs of fetal and newborn rabbits. Morphologic, biochemical, and surface physical development. Am J Pathol. 1968 Jan;52(1):177–210. [PMC free article] [PubMed]
  • Pringle KC. Human fetal lung development and related animal models. Clin Obstet Gynecol. 1986 Sep;29(3):502–513. [PubMed]
  • Asabe K, Toki N, Hashimoto S, Suita S, Sueishi K. An immunohistochemical study of the expression of surfactant apoprotein in the hypoplastic lung of rabbit fetuses induced by oligohydramnios. Am J Pathol. 1994 Sep;145(3):631–639. [PMC free article] [PubMed]
  • Williams MC, Mason RJ. Development of the type II cell in the fetal rat lung. Am Rev Respir Dis. 1977 Jun;115(6 Pt 2):37–47. [PubMed]
  • Snyder JM, Magliato SA. An ultrastructural, morphometric analysis of rabbit fetal lung type II cell differentiation in vivo. Anat Rec. 1991 Jan;229(1):73–85. [PubMed]
  • Cooney TP, Thurlbeck WM. The radial alveolar count method of Emery and Mithal: a reappraisal 1--postnatal lung growth. Thorax. 1982 Aug;37(8):572–579. [PMC free article] [PubMed]
  • Bolender RP, Hyde DM, Dehoff RT. Lung morphometry: a new generation of tools and experiments for organ, tissue, cell, and molecular biology. Am J Physiol. 1993 Dec;265(6 Pt 1):L521–L548. [PubMed]
  • Gundersen HJ, Bendtsen TF, Korbo L, Marcussen N, Møller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sørensen FB, Vesterby A, et al. Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS. 1988 May;96(5):379–394. [PubMed]
  • Hsu SM, Raine L, Fanger H. A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying polypeptide hormones with radioimmunoassay antibodies. Am J Clin Pathol. 1981 May;75(5):734–738. [PubMed]
  • Hashim E, Laberge JM, Chen MF, Quillen EW., Jr Reversible tracheal obstruction in the fetal sheep: effects on tracheal fluid pressure and lung growth. J Pediatr Surg. 1995 Aug;30(8):1172–1177. [PubMed]
  • Reid L, Meyrick B. Etude au microscope électronique du poumon foetal de lapin. Poumon Coeur. 1969;25(3):201–206. [PubMed]
  • Luks FI, Gilchrist BF, Jackson BT, Piasecki GJ. Endoscopic tracheal obstruction with an expanding device in a fetal lamb model: preliminary considerations. Fetal Diagn Ther. 1996 Jan-Feb;11(1):67–71. [PubMed]
  • Scott JE, Yang SY, Stanik E, Anderson JE. Influence of strain on [3H]thymidine incorporation, surfactant-related phospholipid synthesis, and cAMP levels in fetal type II alveolar cells. Am J Respir Cell Mol Biol. 1993 Mar;8(3):258–265. [PubMed]
  • Liu M, Xu J, Tanswell AK, Post M. Stretch-induced growth-promoting activities stimulate fetal rat lung epithelial cell proliferation. Exp Lung Res. 1993 Jul-Aug;19(4):505–517. [PubMed]
  • Brody JS, Burki R, Kaplan N. Deoxyribonucleic acid synthesis in lung cells during compensatory lung growth after pneumonectomy. Am Rev Respir Dis. 1978 Feb;117(2):307–316. [PubMed]
  • Rannels DE, White DM, Watkins CA. Rapidity of compensatory lung growth following pneumonectomy in adult rats. J Appl Physiol Respir Environ Exerc Physiol. 1979 Feb;46(2):326–333. [PubMed]
  • Berger LC, Burri PH. Timing of the quantitative recovery in the regenerating rat lung. Am Rev Respir Dis. 1985 Oct;132(4):777–783. [PubMed]
  • Simnett JD, Fisher JM, Heppleston AG. Tissue-specific inhibition of lung alveolar cell mitosis in organ culture. Nature. 1969 Aug 30;223(5209):944–946. [PubMed]

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