Advertisement

Angiogenesis

, Volume 15, Issue 1, pp 23–32 | Cite as

Spatial dependence of alveolar angiogenesis in post-pneumonectomy lung growth

  • Moritz A. Konerding
  • Barry C. Gibney
  • Jan P. Houdek
  • Kenji Chamoto
  • Maximilian Ackermann
  • Grace S. Lee
  • Miao Lin
  • Akira Tsuda
  • Steven J. Mentzer
Original Paper

Abstract

Growth of the remaining lung after pneumonectomy has been observed in many mammalian species; nonetheless, the pattern and morphology of alveolar angiogenesis during compensatory growth is unknown. Here, we investigated alveolar angiogenesis in a murine model of post-pneumonectomy lung growth. As expected, the volume and weight of the remaining lung returned to near-baseline levels within 21 days of pneumonectomy. The percentage increase in lobar weight was greatest in the cardiac lobe (P < 0.001). Cell cycle flow cytometry demonstrated a peak of lung cell proliferation (12.02 ± 1.48%) 6 days after pneumonectomy. Spatial autocorrelation analysis of the cardiac lobe demonstrated clustering of similar vascular densities (positive autocorrelation) that consistently mapped to subpleural regions of the cardiac lobe. Immunohistochemical staining demonstrated increased cell density and enhanced expression of angiogenesis-related factors VEGFA, and GLUT1 in these subpleural regions. Corrosion casting and scanning electron microscopy 3–6 days after pneumonectomy demonstrated subpleural vessels with angiogenic sprouts. The monopodial sprouts appeared to be randomly oriented along the vessel axis with interbranch distances of 11.4 ± 4.8 μm in the regions of active angiogenesis. Also present within the regions of increased vascular density were frequent “holes” or “pillars” consistent with active intussusceptive angiogenesis. The mean pillar diameter was 4.2 ± 3.8 μm, and the pillars were observed in all regions of active angiogenesis. These findings indicate that the process of alveolar construction involves discrete regions of regenerative growth, particularly in the subpleural regions of the cardiac lobe, characterized by both sprouting and intussusceptive angiogenesis.

Keywords

Scanning electron microscopy Corrosion casting Neoalveolarization Intussusceptive angiogenesis MicroCT 

Abbreviations

2D

2-Dimensional

3D

3-Dimensional

CL

Cardiac lobe

IP

Intraperitoneal

LWI

Lung weight index

MLI

Mean linear intercept

PBS

Phosphate buffered saline

RLL

Right lower lobe

RML

Right middle lobe

RUL

Right upper lobe

SD

Standard deviation

SEM

Scanning electron microscopy

TBW

Total body weight

Notes

Acknowledgments

This work was supported by NIH grants HL75426, HL94567 and HL007734 as well as the Uehara Memorial Foundation and the JSPS Postdoctoral Fellowships for Research Abroad.

References

  1. 1.
    Addis T (1928) Compensatory hypertrophy of the lung after unilateral pneumectomy. J Exp Med 47:51–56PubMedCrossRefGoogle Scholar
  2. 2.
    Tatar-Kiss S, Bardocz S, Kertai P (1984) Changes in l-ornithine decarboxylase activity in regenerating lung lobes. FEBS Lett 175:131–134PubMedCrossRefGoogle Scholar
  3. 3.
    Heuer GJ, Dunn GR (1920) Experimental pneumectomy. Bull Johns Hopkins Hosp 31:31–42Google Scholar
  4. 4.
    Bremer JL (1936) The fate of the remaining lung tissue after lobectomy or pneumonectomy. J Thorac Surg 6:336–343Google Scholar
  5. 5.
    Sery Z, Keprt E, Obrucnik M (1969) Morphometric analysis of late adaptation of residual lung following pneumonectomy in young and adult rabbits. J Thorac Cardiovasc Surg 57:549–557PubMedGoogle Scholar
  6. 6.
    McBride JT (1989) Lung-volumes after an increase in lung distension in pneumonectomized ferrets. J Appl Physiol 67:1418–1421PubMedGoogle Scholar
  7. 7.
    Romanova LK, Leikina EM, Antipova KK (1967) Nucleic acid synthesis and mitotic activity during development of compensatory hypertrophy of lung in rats. Bull Exp Biol Med Ussr 63:303–306CrossRefGoogle Scholar
  8. 8.
    Voswinckel R, Motejl V, Fehrenbach A, Wegmann M, Mehling T, Fehrenbach H, Seeger W (2004) Characterisation of post-pneumonectomy lung growth in adult mice. Eur Respir J 24:524–532PubMedCrossRefGoogle Scholar
  9. 9.
    Fehrenbach H, Voswinickel R, Michl V, Mehling T, Fehrenbach A, Seeger W, Nyengaard JR (2008) Neoalveolarisation contributes to compensatory lung growth following pneumonectomy in mice. Eur Respir J 31:515–522PubMedCrossRefGoogle Scholar
  10. 10.
    Kumar H, Tawhai MH, Hoffman EA, Lin CL (2009) The effects of geometry on airflow in the acinar region of the human lung. J Biomech 42:1635–1642PubMedCrossRefGoogle Scholar
  11. 11.
    Sznitman J, Heimsch T, Wildhaber JH, Tsuda A, Rosgen T (2009) Respiratory flow phenomena and gravitational deposition in a three-dimensional space-filling model of the pulmonary acinar tree. J Biomech Eng Trans Asme 131:1–16CrossRefGoogle Scholar
  12. 12.
    Chang HK, Cheng RT, Farhi LE (1973) Model study of gas-diffusion in alveolar sacs. Respir Physiol 18:386–397PubMedCrossRefGoogle Scholar
  13. 13.
    Tippe A, Tsuda A (2000) Recirculating flow in an expanding alveolar model: experimental evidence of flow-induced mixing of aerosols in the pulmonary acinus. J Aerosol Sci 8:979–986CrossRefGoogle Scholar
  14. 14.
    Thompson DW (1945). The forms of tissues, or cell-aggregates. In: On growth and form. Cambridge University Press, New York, pp 465–565Google Scholar
  15. 15.
    Ciurea D, Gil J (1996) Morphometry of capillaries in three zones of rabbit lungs fixed by vascular perfusion. Anat Rec 244:182–192PubMedCrossRefGoogle Scholar
  16. 16.
    Schittny JC, Mund SI, Stampanoni M (2008) Evidence and structural mechanism for late lung alveolarization. Am J Physiol Lung Cell Mol Physiol 294:L246–L254PubMedCrossRefGoogle Scholar
  17. 17.
    Burri PH (1985) Development and growth of the human lung. In: Fishman AP, Fisher AB (eds) Handbook of physiology. The respiratory system. American Physiological Society, Bethesda, pp 1–46Google Scholar
  18. 18.
    Burri PH (2006) Structural aspects of postnatal lung development—alveolar formation and growth. Biol Neonate 89:313–322PubMedCrossRefGoogle Scholar
  19. 19.
    Zeltner TB, Caduff JH, Gehr P, Pfenninger J, Burri PH (1987) The postnatal-development and growth of the human-lung. I. morphometry. Respir Physiol 67:247–267PubMedCrossRefGoogle Scholar
  20. 20.
    Yan X, Bellotto DJ, Foster DJ, Johnson RL, Hagler HK, Estrera AS, Hsia CCW (2004) Retinoic acid induces nonuniform alveolar septal growth after right pneumonectomy. J Appl Physiol 96:1080–1089PubMedCrossRefGoogle Scholar
  21. 21.
    Takeda SI, Hsia CCW, Wagner E, Ramanathan M, Estrera AS, Weibel ER (1999) Compensatory alveolar growth normalizes gas-exchange function in immature dogs after pneumonectomy. J Appl Physiol 86:1301–1310PubMedGoogle Scholar
  22. 22.
    Landesberg LJ, Ramalingam R, Lee K, Rosengart TK, Crystal RG (2001) Upregulation of transcription factors in lung in the early phase of postpneumonectomy lung growth. Am J Physiol Lung Cell Mol Physiol 281:L1138–L1149PubMedGoogle Scholar
  23. 23.
    Kaza AK, Kron IL, Leuwerke SM, Tribble CG, Laubach VE (2002) Keratinocyte growth factor enhances post-pneumonectomy lung growth by alveolar proliferation. Circulation 106:I120–I124PubMedGoogle Scholar
  24. 24.
    Sakamaki Y, Matsumoto K, Mizuno S, Miyoshi S, Matsuda H, Nakamura T (2002) Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice. Am J Respir Cell Mol Biol 26:525–533PubMedGoogle Scholar
  25. 25.
    Zhang Q, Bellotto DJ, Ravikumar P, Moe OW, Hogg RT, Hogg DC, Estrera AS, Johnson RL Jr, Hsia CC (2007) Postpneumonectomy lung expansion elicits hypoxia-inducible factor-1alpha signaling. Am J Physiol Lung Cell Mol Physiol 293:L497–L504PubMedCrossRefGoogle Scholar
  26. 26.
    Leuwerke SM, Kaza AK, Tribble CG, Kron IL, Laubach VE (2002) Inhibition of compensatory lung growth in endothelial nitric oxide synthase-deficient mice. Am J Physiol Lung Cell Mol Physiol 282:L1272–L1278PubMedGoogle Scholar
  27. 27.
    Yuan SZ, Hannam V, Belcastro R, Cartel N, Cabacungan J, Wang JX, Diambomba Y, Johnstone L, Post M, Tanswell AK (2002) A role for platelet-derived growth factor-BB in rat postpneumonectomy compensatory lung growth. Pediatr Res 52:25–33PubMedCrossRefGoogle Scholar
  28. 28.
    Jancelewicz T, Grethel EJ, Chapin CJ, Clifton MS, Nobuhara KK (2008) Vascular endothelial growth factor isoform and receptor expression during compensatory lung growth. J Surg Res 160:107–113PubMedCrossRefGoogle Scholar
  29. 29.
    Lin M, Chamoto K, Gibney B, Lee GS, Collings-Simpson D, Houdek J, Konerding MA, Tsuda A, Mentzer SJ (2011) Angiogenesis gene expression in murine endothelial cells during post-pneumonectomy lung growth. Respir Res (in press)Google Scholar
  30. 30.
    Paxson JA, Parkin CD, Iyer LK, Mazan MR, Ingenito EP, Hoffman AM (2009) Global gene expression patterns in the post-pneumonectomy lung of adult mice. Respir Res 10:1–15CrossRefGoogle Scholar
  31. 31.
    Wolff JC, Wilhelm J, Fink L, Seeger W, Voswinckel R (2010) Comparative gene expression profiling of post-natal and post-pneumonectomy lung growth. Eur Respir J 35:655–666PubMedCrossRefGoogle Scholar
  32. 32.
    Gibney B, Lee GS, Houdek J, Lin M, Chamoto K, Konerding MA, Tsuda A, Mentzer SJ (2011) Dynamic determination of oxygenation and lung compliance in murine pneumonectomy. Exp Lung Res 37:301–309PubMedCrossRefGoogle Scholar
  33. 33.
    Wersto RP, Chrest FJ, Leary JF, Morris C, Stetler-Stevenson M, Gabrielson E (2001) Doublet discrimination in DNA cell-cycle analysis. Cytometry 46:296–306PubMedCrossRefGoogle Scholar
  34. 34.
    Marwan N, Kurths J, Thomsen JS, Felsenberg D, Saparin P (2009) Three-dimensional quantification of structures in trabecular bone using measures of complexity. Phys Rev E 79:1–11Google Scholar
  35. 35.
    Wald MJ, Vasilic B, Saha PK, Wehrli FW (2007) Spatial autocorrelation and mean intercept length analysis of trabecular bone anisotropy applied to in vivo magnetic resonance imaging. Med Phys 34:1110–1120PubMedCrossRefGoogle Scholar
  36. 36.
    Yilmaz C, Ravikumar P, Dane DM, Bellotto DJ, Johnson RL, Hsia CCW (2009) Noninvasive quantification of heterogeneous lung growth following extensive lung resection by high-resolution computed tomography. J Appl Physiol 107:1569–1578PubMedCrossRefGoogle Scholar
  37. 37.
    Ravikumar P, Yilmaz C, Dane DM, Johnson RL, Estrera AS, Hsia CCW (2007) Developmental signals do not further accentuate nonuniform postpneumonectomy compensatory lung growth. J Appl Physiol 102:1170–1177PubMedCrossRefGoogle Scholar
  38. 38.
    Ochs M, Nyengaard LR, Lung A, Knudsen L, Voigt M, Wahlers T, Richter J, Gundersen HJG (2004) The number of alveoli in the human lung. Am J Respir Crit Care Med 169:120–124Google Scholar
  39. 39.
    Weibel ER (1963) Geometry and dimensions of alveolar capillary network. In: Morphometry of the human lung. Academic Press, New York, pp 73–89Google Scholar
  40. 40.
    Campbell H, Tomkeieff SI (1952) Calculation of the internal surface of a lung. Nature 170:117CrossRefGoogle Scholar
  41. 41.
    Schraufnagel DE, Malik R, Goel V, Ohara N, Chang SW (1997) Lung capillary changes in hepatic cirrhosis in rats. Am J Physiol Lung Cell Mol Physiol 272:L139–L147Google Scholar
  42. 42.
    Schraufnagel DE (1990) Monocrotaline-induced angiogenesis. Differences in the bronchial and pulmonary vasculature. Am J Pathol 137:1083–1090PubMedGoogle Scholar
  43. 43.
    Wagner EM, Petrache I, Schofield B, Mitzner W (2006) Pulmonary ischemia induces lung remodeling and angiogenesis. J Appl Physiol 100:587–593PubMedCrossRefGoogle Scholar
  44. 44.
    Schraufnagel DE, Sekosan M, McGee T, Thakkar MB (1996) Human alveolar capillaries undergo angiogenesis in pulmonary veno-occlusive disease. Eur Respir J 9:346–350PubMedCrossRefGoogle Scholar
  45. 45.
    Caduff JH, Fischer LC, Burri PH (1986) Scanning electron microscope study of the developing microvasculature in the postnatal rat lung. Anat Rec 216:154–164PubMedCrossRefGoogle Scholar
  46. 46.
    Burri PH, Tarek MR (1990) A novel mechanism of capillary growth in the rat pulmonary microcirculation. Anat Rec 228:35–45PubMedCrossRefGoogle Scholar
  47. 47.
    Lee GS, Filipovic N, Lin M, Gibney BC, Simpson DC, Konerding MA, Tsuda A, Mentzer SJ (2011) Intravascular pillars and pruning in the extraembryonic vessels of chick embryos. Dev Dyn 240:1335–1343PubMedCrossRefGoogle Scholar
  48. 48.
    Fernandez LG, Le Cras TD, Ruiz M, Glover DK, Kron IL, Laubach VE (2007) Differential vascular growth in postpneumonectomy compensatory lung growth. J Thorac Cardiovasc Surg 133:309–316PubMedCrossRefGoogle Scholar
  49. 49.
    Rannels DE, Stockstill B, Mercer RR, Crapo JD (1991) Cellular-changes in the lungs of adrenalectomized rats following left pneumonectomy. Am J Respir Cell Mol Biol 5:351–362PubMedGoogle Scholar
  50. 50.
    Sekhon HS, Thurlbeck WM (1992) A comparative-study of postpneumonectomy compensatory lung response in growing male and female rats. J Appl Physiol 73:446–451PubMedGoogle Scholar
  51. 51.
    Rannels DE, White DM, Watkins CA (1979) Rapidity of compensatory lung growth following pneumonectomy in adult rats. J Appl Physiol 46:326–333PubMedGoogle Scholar
  52. 52.
    Cagle PT, Langston C, Goodman JC, Thurlbeck WM (1990) Autoradiographic assessment of the sequence of cellular proliferation in postpneumonectomy lung growth. Am J Respir Cell Mol Biol 3:153–158PubMedGoogle Scholar
  53. 53.
    Thet LA, Law DJ (1984) Changes in cell number and lung morphology during early postpneumonectomy lung growth. J Appl Physiol 56:975–978PubMedGoogle Scholar
  54. 54.
    Fisher JM, Simnett JD (1973) Morphogenetic and proliferative changes in regenerating lung of rat. Anat Rec 176:389–395PubMedCrossRefGoogle Scholar
  55. 55.
    Brody JS, Burki R, Kaplan N (1978) Deoxyribonucleic-acid synthesis in lung-cells during compensatory lung growth after pneumonectomy. Am Rev Respir Dis 117:307–316PubMedGoogle Scholar
  56. 56.
    Holmes C, Thurlbeck WM (1979) Normal lung growth and response after pneumonectomy in rats at various ages. Am Rev Respir Dis 120:1125–1136PubMedGoogle Scholar
  57. 57.
    Foster DJ, Yan X, Bellotto DJ, Moe OW, Hagler HK, Estrera AS, Hsia CCW (2002) Expression of epidermal growth factor and surfactant proteins during postnatal and compensatory lung growth. Am J Physiol Lung Cell Mol Physiol 283:L981–L990PubMedGoogle Scholar
  58. 58.
    Nattie EE, Wiley CW, Bartlett D (1974) Adaptive growth of lung following pneumonectomy in rats. J Appl Physiol 37:491–495PubMedGoogle Scholar
  59. 59.
    Chamoto K, Gibney BC, Lee GS, Lin M, Simpson DC, Voswinckel R, Konerding MA, Tsuda A, Mentzer SJ (2011) CD34+ progenitor to endothelial cell transition in post-pneumonectomy angiogenesis. Am J Resp Cell Mol Biol (in press)Google Scholar
  60. 60.
    Chamoto K, Gibney BC, Lee GS, Lin M, Konerding MA, Tsuda A, Mentzer SJ (2011) Alveolar macrophage dynamics in post-pneumonectomy lung growth. J Immunol (in revision)Google Scholar
  61. 61.
    Zeltner TB, Bertacchini M, Messerli A, Burri PH (1990) Morphometric estimation of regional differences in the rat lung. Exp Lung Res 16:145–158PubMedCrossRefGoogle Scholar
  62. 62.
    Marchand P, Gilroy JC, Wilson VH (1950) An anatomical study of the bronchial vascular system and its variations in disease. Thorax 5:207–221PubMedCrossRefGoogle Scholar
  63. 63.
    Herrick SE, Mutsaers SE (2004) Mesothelial progenitor cells and their potential in tissue engineering. Int J Biochem Cell Biol 36:621–642PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Moritz A. Konerding
    • 1
  • Barry C. Gibney
    • 2
  • Jan P. Houdek
    • 1
  • Kenji Chamoto
    • 2
  • Maximilian Ackermann
    • 1
  • Grace S. Lee
    • 2
  • Miao Lin
    • 2
  • Akira Tsuda
    • 3
  • Steven J. Mentzer
    • 2
  1. 1.Institute of Functional and Clinical AnatomyUniversity Medical Center of Johannes Gutenberg-UniversityMainzGermany
  2. 2.Laboratory of Adaptive and Regenerative BiologyBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Molecular and Integrative Physiological SciencesHarvard School of Public HealthBostonUSA

Personalised recommendations