Endocrine Pathology

, Volume 15, Issue 2, pp 91–106 | Cite as

Immunomodulatory functions of the diffuse neuroendocrine system: Implications for bronchopulmonary dysplasia



Pulmonary neuroendocrine (NE) cells are believed to be the precursor of NE lung carcinomas, including well-differentiated (carcinoids) and moderately/poorly differentiated (atypical carcinoids and small-cell carcinomas, SCLCs) subtypes. In early studies, we determined mechanisms by which NE cell-derived peptides such as bombesin-like peptide (BLP) promote normal fetal lung development. Postnatally, BLP may normally regulate perinatal adaptation of the pulmonary circulation. However, elevated BLP levels in premature infants shortly after birth predict which infants are at high risk for developing bronchopulmonary dysplasia (BPD, chronic lung disease of newborns). An anti-BLP blocking antibody abrogates clinical and pathological evidence of lung injury in two baboon models of BPD. These observations indicate that BLP mediates lung injury in BPD, supporting a role for BLP as pro-inflammatory cytokines. We have directly tested the effects of BLP on eliciting inflammatory cell infiltrates in vivo. Surprisingly, mast cells are the major responding cell population. These data suggest that the diffuse NE system may be a newly recognized component of innate immunity in multiple organ systems. We speculate that overproduction of NE cell-derived peptides such as BLP may be responsible for a variety of chronic inflammatory disorders.

Key Words

Bombesin lung development lung injury mast cells innate immunity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Anastasi A, Erspamer V, Bucci M. Isolation and structure of bombesin and alytesin, two analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia 27:166–169, 1971.PubMedCrossRefGoogle Scholar
  2. 2.
    McDonald TJ, Jornvall H, Nilsson G, Vagne M, Ghatei M, Bloom SR, Mutt V. Characterization of a gastrin-releasing peptide from porcine non-antral gastric tissue. Biochem Biophys Res Commun 90:227–233, 1979.PubMedCrossRefGoogle Scholar
  3. 3.
    Spindel ER, Chin WW, Price J, Rees LH, Besser GM, Habener JF. Cloning and characterization of cDNAs encoding human gastrin-releasing peptide. Proc Natl Acad Sci USA 81:5699–5703, 1984.PubMedCrossRefGoogle Scholar
  4. 4.
    Sausville EA, Lebacq-Verheyden AM, Spindel ER, Cuttitta F, Gazdar AF, Battey JF. Expression of the gastrin-releasing peptide gene in human small cell lung cancer: Evidence for alternative processing resulting in three distinct mRNAs. J Biol Chem 261:2451–2457, 1986.PubMedGoogle Scholar
  5. 5.
    Lebacq-Verheyden AM, Krystal G, Sartor O, Way J, Battey JF. The prepro gastrin releasing peptide gene is transcribed from two initiation sites in the brain. Mol Endocrinol 2:556–563, 1988.PubMedGoogle Scholar
  6. 6.
    Sunday ME, Kaplan LM, Motoyama E, Chin WW, Spindel ER. Biology of disease: Gastrin-releasing peptide (mammalian bombesin) gene expression in health and disease. Lab Invest 59:5–24, 1988.PubMedGoogle Scholar
  7. 7.
    Nagalla SR, Barry BJ, Spindel ER. Cloning of complementary DNAs encoding the amphibian bombesin-like peptides Phe8 and Leu8 phyllolitorin from Phyllomedusa sauvagei: potential role of U to C RNA editing in generating neuropeptide diversity. Mol Endocrinol 8:943–951, 1994.PubMedCrossRefGoogle Scholar
  8. 8.
    Erspamer V. Amphibian skin peptides in mammals—looking ahead. Trends Neurosci 6:200–201, 1983.CrossRefGoogle Scholar
  9. 9.
    Minna J. Bombesin receptor gene cloned. Science 249:1377, 1990.CrossRefGoogle Scholar
  10. 10.
    Battey J, Wada E. Two distinct receptor subtypes for mammalian bombesin-like peptides. Trends Neurosci 14:524–528, 1991.PubMedCrossRefGoogle Scholar
  11. 11.
    Battey JF, Way JM, Corjay MH, et al. Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cells. Proc Natl Acad Sci USA 88:395–399, 1991.PubMedCrossRefGoogle Scholar
  12. 12.
    Spindel ER, Giladi E, Brehm P, Goodman RH, Segerson TP. Cloning and functional characterization of a complementary DNA encoding the murine fibroblast bombesin/gastrin-releasing peptide receptor. Mol Endocrinol 4:1956–1963, 1990.PubMedCrossRefGoogle Scholar
  13. 13.
    Lach E, Haddad EB, Gies JP. Contractile effect of bombesin on guinea pig lung in vitro: involvement of gastrin-releasing peptide-preferring receptors. Am J Physiol 264:L80-L86, 1993.PubMedGoogle Scholar
  14. 14.
    Gorbulev V, Akhundova A, Buchner H, Fahrenholz F. Molecular cloning of a new bombesin receptor subtype expressed in uterus during pregnancy. Eur J Biochem 208:405–410, 1992.PubMedCrossRefGoogle Scholar
  15. 15.
    Fathi Z, Corjay MH, Shapira H, et al. BRS-3: A novel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells. J Biol Chem 268:5979–5984, 1993.PubMedGoogle Scholar
  16. 16.
    Shan L, Emanuel RL, Dewald D, et al. Bombesin-like peptide (BLP) receptor gene expression, regulation, and function in fetal murine lung. Am J Physiol Lung Cell Mol Physiol 286:L165–173, 2004.PubMedCrossRefGoogle Scholar
  17. 17.
    Fischer JB, Schonbrunn A. The bombesin receptor is coupled to a guanine nucleotide-binding protein which is insensitive to pertussis and cholera toxins. J Biol Chem 263:2808–2816, 1988.PubMedGoogle Scholar
  18. 18.
    Zachary I, Rozengurt E. Focal adhesion kinase (p125FAK): A point of convergence in the action of neuropeptides, integrins, and oncogenes. Cell 71:891–894, 1992.PubMedCrossRefGoogle Scholar
  19. 19.
    Rozengurt E. Neuropeptides as cellular growth factors: role of multiple signalling pathways. Eur J Clin Invest 21:123–134, 1991.PubMedGoogle Scholar
  20. 20.
    Wada E, Battey J, Wray S. Bombesin receptor gene expression in rat embryos: transient GRP-R gene expression in the posterior pituitary. Mol Cell Neurosci 4:13–24, 1993.CrossRefPubMedGoogle Scholar
  21. 21.
    King KA, Torday JS, Sunday ME. Bombesin and [leu8]phyllolitorin promote fetal mouse lung branching morphogenesis via a specific receptor-mediated mechanism. Proc Natl Acad Sci USA 92:4357–4361, 1995.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang D, Yeger H, Cutz E. Expression of gastrin releasing peptide receptor gene in developing lung. Am J Respir Cell Mol Biol 14:409–416, 1996.PubMedGoogle Scholar
  23. 23.
    Li K, Nagalla SR, Spindel ER. A rhesus monkey model to characterize the role of gastrin-releasing peptide (GRP) in lung development. J Clin Invest 94:1605–1615, 1994.PubMedGoogle Scholar
  24. 24.
    Brimhall BB, Sikorski KA, Torday J, Shahsafaei A, Haley KJ, Sunday ME. Syntaxin 1A is transiently expressed in fetal lung mesenchymal cells: potential developmental roles. Am J Physiol Lung Cell Mol Physiol 277:L401-L411, 1999.Google Scholar
  25. 25.
    Sunday ME, Hua J, Dai HB, Nusrat A, Torday JS. Bombesin increases fetal lung growth and maturation in utero and in organ culture. Am J Respir Cell Mol Biol 3:199–205, 1990.PubMedGoogle Scholar
  26. 26.
    Wharton J, Polak JM, Bloom SR, et al. Bombesin-like immunoreactivity in the lung. Nature 273:769–770, 1978.PubMedCrossRefGoogle Scholar
  27. 27.
    Minna JD, Cuttitta F, Battey JF, et al. Gastrin-releasing peptide and other autocrine growth factors in lung cancer: pathogenetic and treatment implications. In: DeVita VT, Hellman S, Rosenberg SA, eds. Important Advances in Oncology, Philadelphia, PA: Lippincott, 1988; 55–64.Google Scholar
  28. 28.
    Siegfried JM, Guentert PJ, Gaither AL. Effects of bombesin and gastrin-releasing peptide on human bronchial epithelial cells from a series of donors: Individual variation and modulation by bombesin analogs. Anat Rec 236:241–247, 1993.PubMedCrossRefGoogle Scholar
  29. 29.
    Rozengurt E, Sinnett-Smith J. Early signals underlying the induction of the c-fos and c-myc genes in quiescent fibroblasts: studies with bombesin and other growth factors. Prog Nucleic Acid Res Mol Biol 35:261–295, 1988.PubMedGoogle Scholar
  30. 30.
    Cuttitta F, Carney DN, Mulshine J, et al. Bombesin-like peptides can function as autocrine growth factors in human small cell cancer. Nature 316:823–826, 1985.PubMedCrossRefGoogle Scholar
  31. 31.
    Impicciatore M, Bertaccini G. The bronchoconstrictor action of the tetradecapeptide bombesin in the guinea-pig. J Pharm Pharmacol 25:872–875, 1973.PubMedGoogle Scholar
  32. 32.
    Erspamer GF, Mazzanti G, Farruggia G, Nakajima T, Yanaihara N. Parallel bioassay of litorin and phyllolitorins on smooth muscle preparations. Peptides 5:765–768, 1984.CrossRefGoogle Scholar
  33. 33.
    Sunday ME, Hua J, Reyes B, Masui H, Torday JS. Anti-bombesin antibodies modulate fetal mouse lung growth and maturation in utero and in organ cultures. Anat Rec 236:25–32, 1993.PubMedCrossRefGoogle Scholar
  34. 34.
    Kim JS, McKinnis VS, White SR. Migration of guinea pig airway epithelial cells in response to bombesin analogues. Am J Respir Cell Mol Biol 16:259–266, 1997.PubMedGoogle Scholar
  35. 35.
    Ruff M, Schiffmann E, Terranova V, Pert CB. Neuropeptides are chemoattractants for human tumor cells and monocytes: A possible mechanism for metastasis. Clin Immunol Immunopathol 37:387–396, 1985.PubMedCrossRefGoogle Scholar
  36. 36.
    De la Fuente M, Del Rio M, Ferrandez MD, Hernanz A. Modulation of phagocytic function in murine peritoneal macrophages by bombesin, gastrin-releasing peptide and neuromedin C. Immunology 73:205–211, 1991.PubMedGoogle Scholar
  37. 37.
    Meloni F, Ballabio P, Bianchi L, et al. Bombesin enhances monocyte and macrophage activities: possible role in the modulation of local pulmonary defenses in chronic bronchitis. Respiration 63:28–34, 1996.PubMedGoogle Scholar
  38. 38.
    Meloni F, Bertoletti R, Corsico A, Di Fazio P, Cecchettin M, Gialdroni-Grassi G. Bombesin/gastrin releasing peptide levels of peripheral mononuclear cells, monocytes and alveolar macrophages in chronic bronchitis. Int J Tissue Reactions 14:195–201, 1992.Google Scholar
  39. 39.
    Yule KA, White SR. Migration of 3T3 and lung fibroblasts in response to calcitonin gene-related peptide and bombesin. Exp Lung Res 25:261–273, 1999.PubMedCrossRefGoogle Scholar
  40. 40.
    Kelley MJ, Linnoila RI, Avis IL, et al. Antitumor activity of a monoclonal antibody directed against gastrin-releasing peptide in patients with small cell lung cancer. Chest 112:256–261, 1997.PubMedGoogle Scholar
  41. 41.
    Wang LH, Coy DH, Taylor JE, et al. Desmethionine alkylamide bombesin analogues: a new class of bombesin receptor antagonists with potent antisecretory activity in pancreatic acini and antimitotic activity in Swiss 3T3 cells. Biochem 29:616–622, 1990.CrossRefGoogle Scholar
  42. 42.
    Wang LH, Coy DH, Taylor JE, et al. Desmethionine alkylamide bombesin analogues: a new class of bombesin. Biochem 29:616–622, 1990.CrossRefGoogle Scholar
  43. 43.
    King KA, Hua J, Torday JS, et al. CD10/Neutral endopeptidase regulates fetal lung growth and maturation in utero by potentiating endogenous bombesin-like peptides. J Clin Invest 91:1969–1973, 1993.PubMedGoogle Scholar
  44. 44.
    Sunday ME, Hua J, Torday J, Reyes B, Shipp MA. CD10/neutral endopeptidase 24.11 in developing human fetal lung: patterns of expression and modulation of peptide-mediated proliferation. J Clin Invest 90:2517–2525, 1992.PubMedGoogle Scholar
  45. 45.
    Emanuel RL, Torday JS, Mu Q, Asokananthan N, Sikorski KA, Sunday ME. Bombesin-like peptides and receptors in normal fetal baboon lung: roles in lung growth and maturation. Am J Physiol 277:L1003-L1017, 1999.PubMedGoogle Scholar
  46. 46.
    Aguayo SM, Kane MA, King TE, Schwarz MI, Grauer L, Miller YE. Increased levels of bombesin-like peptides in the lower respiratory tract of asymptomatic cigarette smokers. J Clin Invest 84:1105–1113, 1989.PubMedGoogle Scholar
  47. 47.
    Fraslon C, Bourbon JR. Comparison of effects of epidermal and insulin-like growth factors, gastrin releasing peptide and retinoic acid on fetal lung cell growth and maturation in vitro. Biochim Biophysica Acta 1123:65–75, 1992.Google Scholar
  48. 48.
    Koh S, Yamamoto A, Inoue A, et al. Immunoelectron microscopic localization of the HPC-1 antigen in rat cerebellum. J Neurocytol 22:995–1005, 1993.PubMedCrossRefGoogle Scholar
  49. 49.
    Masaki R, Yamamoto A, Akagawa K, Tashiro Y. Important roles of the C-terminal portion of HPC-1/syntaxin 1A in membrane anchoring and intracellular localization. J Biochem 124:311–318, 1998.PubMedGoogle Scholar
  50. 50.
    Inoue A, Akagawa K. Neuron-specific expression of a membrane protein, HPC-1: tissue distribution, and cellular and subcellular localization of immunoreactivity and mRNA. Molec Brain Res 19:121–128, 1993.PubMedCrossRefGoogle Scholar
  51. 51.
    Sesack SR, Snyder CL. Cellular and subcellular localization of syntaxin-like immunore-activity in the rat striatum and cortex. Neuroscience 67:993–1007, 1995.PubMedCrossRefGoogle Scholar
  52. 52.
    Akagawa K, Barnstable CJ. Identification and characterization of cell types in monolayer cultures of rat retina using monoclonal antibodies. Brain Res 383:110–120, 1986.PubMedCrossRefGoogle Scholar
  53. 53.
    Kong Y, Glickman J, Subramaniam M, et al. Functional diversity of notch family genes in fetal lung development. Am J Physiol Lung Cell Mol Physiol 286:L1075–1083, 2004.PubMedCrossRefGoogle Scholar
  54. 54.
    Jan YN, Jan LY. HLH proteins, fly neurogenesis, and vertebrate myogenesis. Cell 75:827–830, 1993.PubMedCrossRefGoogle Scholar
  55. 55.
    Wakamatsu Y, Maynard TM, Weston JA. Fate determination of neural crest cells by NOTCH-mediated lateral inhibition and asymmetrical cell division during gangliogenesis. Development 127:2811–2821, 2000.PubMedGoogle Scholar
  56. 56.
    Campos-Ortega JA. Genetic and molecular bases of neurogenesis in Drosophila melanogaster. Annu Rev Neurosci 14:399–420, 1991.PubMedCrossRefGoogle Scholar
  57. 57.
    Isaac DD, Andrew DJ. Tubulogenesis in Drosophila: a requirement for the trachealess gene product. Genes & Develop 10:103–117, 1996.CrossRefGoogle Scholar
  58. 58.
    Kent G, Iles R, Bear CE, et al. Lung disease in mice with cystic fibrosis. J Clin Invest 100:3060–3069, 1997.PubMedGoogle Scholar
  59. 59.
    Artavanis-Tsakonas S, Delidakis C, Fehon RG. The notch locus and the cell biology of neuroblast segregation. Annu Rev Cell Biol 7:427–452, 1991.PubMedCrossRefGoogle Scholar
  60. 60.
    Fehon RG, Johansen K, Rebay I, Artavanis-Tsakonas S. Complex cellular and subcellular regulation of Notch expression during embryonic and imaginal development of Drosophila: implications for Notch function. J Cell Biol 113:657–669, 1991.PubMedCrossRefGoogle Scholar
  61. 61.
    Ellisen LW, Bird J, West DC, et al. TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649–661, 1991.PubMedCrossRefGoogle Scholar
  62. 62.
    Schroeder T, Just U. Notch signalling via RBP-J promotes myeloid differentiation. EMBO J 19:2558–2568, 2000.PubMedCrossRefGoogle Scholar
  63. 63.
    Anderson AC, Robey EA, Huang YH. Notch signaling in lymphocyte development. Curr Opin Genetics & Develop 11:554–560, 2001.CrossRefGoogle Scholar
  64. 64.
    Karanu FN, Murdoch B, Miyabayashi T, et al. Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells. Blood 97:1960–1967, 2001.PubMedCrossRefGoogle Scholar
  65. 65.
    Pui JC, Allman D, Xu L, et al. Notch 1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11:299–308, 1999.PubMedCrossRefGoogle Scholar
  66. 66.
    Aster J, Pear W, Hasserjian R, et al. Functional analysis of the TAN-1 gene, a human homolog of Drosophila notch. Cold Spring Harbor Symp Quant Biol 59:125–136, 1994.PubMedGoogle Scholar
  67. 67.
    Rangarajan A, Talora C, Okuyama R, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20:3427–3436, 2001.PubMedCrossRefGoogle Scholar
  68. 68.
    Jaleco AC, Neves H, Hooijberg E, et al. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J Exp Med 194:991–1002, 2001.PubMedCrossRefGoogle Scholar
  69. 69.
    Gridley T. Notch signaling during vascular development. Proc Natl Acad Sci USA 98:5377–5378, 2001.PubMedCrossRefGoogle Scholar
  70. 70.
    Austin CP, Feldman DE, Ida JA, Jr., Cepko CL. Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch. Development 121:3637–3650, 1995.PubMedGoogle Scholar
  71. 71.
    Borges M, Linnoila RI, van de Velde HJ, et al. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 386:852–855, 1997.PubMedCrossRefGoogle Scholar
  72. 72.
    Han RNN, Mawdsley C, Souza P, Tanswell AK, Post M. Platelet-derived growth factors and growth-related genes in rat lung. III. Immunolocalization during fetal development. Pediatr Res 31:323–329, 1992.PubMedGoogle Scholar
  73. 73.
    Bostrom H, Willetts K, Pekny M, et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85:863–873, 1996.PubMedCrossRefGoogle Scholar
  74. 74.
    Souza P, Sedlackova L, Kuliszewski M, et al. Antisense oligodeoxynucleotides targeting PDGF-B mRNA inhibit cell proliferation during embryonic rat lung development. Development 120:2163–2173, 1994.PubMedGoogle Scholar
  75. 75.
    Souza P, Tanswell AK, Post M. Different roles for PDGF-α and -β receptors in embryonic lung development. Am J Respir Cell Mol Biol 15:551–562, 1996.PubMedGoogle Scholar
  76. 76.
    Plopper CG, St. George JA, Read LC, et al. Acceleration of alveolar type II cell differentiation in fetal rhesus monkey lung by administration of EGF. Am J Physiol Lung Cell Mol Physiol 262:L313-L321, 1992.Google Scholar
  77. 77.
    Sen N, Cake MH. Enhancement of disaturated phosphatidylcholine synthesis by epidermal growth factor in cultured fetal lung cells involves a fibroblast-epithelial cell interaction. Am J Respir Cell Mol Biol 5:337–343, 1991.PubMedGoogle Scholar
  78. 78.
    Raaberg L, Nex E, Buckley S, Luo W, Snead ML, Warburton D. Epidermal growth factor transcription, translation, and signal transduction by rat type II pneumocytes in culture. Am J Resp Cell Mol Biol 6:44–49, 1992.Google Scholar
  79. 79.
    Sunday ME. Bioactive peptides and lung development. In: Gaultier C, Bourbon JR, Post M, eds. Lung Development, New York, Oxford: Oxford University Press, 1999:304–326.Google Scholar
  80. 80.
    Johnson DE, Wobken JD, Landrum BG. Changes in bombesin, calcitonin and serotonin immunoreactive pulmonary neuroendocrine cells in cystic fibrosis and following prolonged mechanical ventilation. Am Rev Respir Dis 137:123–131, 1988.PubMedGoogle Scholar
  81. 81.
    Aguayo SM, King TE, Waldron JA, Sherritt KM, Kane MA, Miller YE. Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. J Clin Invest 86:838–844, 1990.PubMedGoogle Scholar
  82. 82.
    Bousbaa H, Fleury-Feith J. Effects of a longstanding challenge on pulmonary neuroendocrine cells of actively sensitized guinea pigs. Am Rev Respir Dis 144:714–717, 1991.PubMedGoogle Scholar
  83. 83.
    Sunday ME, Willett CG. Induction and spontaneous regression of intense pulmonary neuroendocrine cell differentiation in a model of preneoplastic lung injury. Cancer Res 52(suppl):2677S-2686S, 1992.PubMedGoogle Scholar
  84. 84.
    Sunday ME, Willett CG, Patidar K, Graham SA, Kelly D. Modulation of oncogene and tumor suppressor gene expression in a hamster model of chronic lung injury with varying degrees of pulmonary neuroendocrine cell hyperplasia. Lab Invest 70:875–888, 1994.PubMedGoogle Scholar
  85. 85.
    Haley KJ, Patidar K, Zhang F, Emanuel RL, Sunday ME. Tumor necrosis factor induces neuroendocrine differentiation in small cell lung carcinoma cell lines. Am J Physiol Lung Cell Mol Physiol 275:L311-L321, 1998.Google Scholar
  86. 86.
    Mabry M, Nakagawa T, Nelkin BD, et al. v-Ha-ras oncogene insertion: A model for tumor progression of human small cell lung cancer. Proc Natl Acad Sci USA 85:6523–6527, 1988.PubMedCrossRefGoogle Scholar
  87. 87.
    Sunday ME, Haley KJ, Sikorski K, et al. Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms. Oncogene 18:4336–4347, 1999.PubMedCrossRefGoogle Scholar
  88. 88.
    Johnston D, Hatzis D, Sunday ME. Expression of v-Ha-ras driven by the calcitonin/calcitonin gene-related peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma. Oncogene 16:167–177, 1998.PubMedCrossRefGoogle Scholar
  89. 89.
    Mabry M, Nakagawa T, Baylin S, Pettengill O, Sorenson G, Nelkin B. Insertion of the v-Ha-ras oncogene induces differentiation of calcitonin-producing human small cell lung cancer. J Clin Invest 84:194–199, 1989.PubMedGoogle Scholar
  90. 90.
    Slebos RJC, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 323:561–565, 1990.PubMedCrossRefGoogle Scholar
  91. 91.
    Sunday ME, Willett CG, Graham SA, Oreffo VIC, Linnoila RI, Witschi H. Histochemical characterization of non-neuroendocrine tumors and neuroendocrine cell hyperplasia induced in hamster lung by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone with or without hyperoxia. Am J Pathol 147:740–752, 1995.PubMedGoogle Scholar
  92. 92.
    Johnson DE, Anderson WR, Burke BA. Pulmonary neuroendocrine cells in pediatric lung disease: alterations in airway structure in infants with bronchopulmonary dysplasia. Anat Rec 236:115–119, 1993.PubMedCrossRefGoogle Scholar
  93. 93.
    Sunday ME. Neuropeptides and lung development. In: McDonald JA, ed. Lung Growth and Development, New York: Dekker, 1997;401–494.Google Scholar
  94. 94.
    Youngson C, Nurse C, Yeger H, Cutz E. Oxygen sensing in airway chemoreceptors. Nature 365:153–155, 1993.PubMedCrossRefGoogle Scholar
  95. 95.
    Northway WH, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline membrane disease. N Engl J Med 276:357–368, 1967.PubMedCrossRefGoogle Scholar
  96. 96.
    Johnson DE, Lock JE, Elde RP, Thompson TR. Pulmonary neuroendocrine cells in hyaline membrane disease and bronchopulmonary dysplasia. Pediatr Res 16:446–454, 1982.PubMedGoogle Scholar
  97. 97.
    Parad RB, Berger TM. Chronic lung disease. In: Cloherty JP, Stark AR, eds. Manual of neonatal care. Philadelphia-New York: Lippincott-Raven, 1998;378–388.Google Scholar
  98. 98.
    Hansen T, Corbet A. Chronic lung disease—bronchopulmonary dysplasia. In: Taeusch HW, Ballard RA, Avery ME, eds. Diseases of the newborn. Toronto: W.B. Saunders Co., 1991;519–526.Google Scholar
  99. 99.
    Abman SH, Groothius JR. Pathophysiology and treatment of bronchopulmonary dysplasia. Current issues. Pediatr Clin North Am 41:277–315, 1994.PubMedGoogle Scholar
  100. 100.
    Ireys HT, Anderson GF, Shaffer TJ, Neff JM. Expenditures for care of children with chronic illnesses enrolled in the Washington State Medicaid program, fiscal year 1993. Pediatrics 100:197–204, 1997.PubMedCrossRefGoogle Scholar
  101. 101.
    Jobe AH. Pulmonary surfactant therapy. N Engl J Med 328:861–868, 1993.PubMedCrossRefGoogle Scholar
  102. 102.
    Jobe AH, Mitchell BR, Gunkel H. Beneficial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants. Am J Obstet Gynecol 168:508–513, 1993.PubMedGoogle Scholar
  103. 103.
    Parker RA, Lindstrom DP, Cotton RB. Improved survival accounts for most, but not all of the increase in bronchopulmonary dysplasia. Pediatrics 90:663–668, 1992.PubMedGoogle Scholar
  104. 104.
    Avery ME, Tooley WH, Keller JB, et al. Is chronic lung disease in low birth weight infants preventable? A survey of eight centers. Pediatr 79:26–30, 1987.Google Scholar
  105. 105.
    Watterberg KL, Derners LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatr 97:210–215, 1996.Google Scholar
  106. 106.
    Konishi M, Fujiwara T, Naito T, et al. Surfactant replacement therapy in neonatal respiratory distress syndrome. Eur J Pharmacol 147:20–25, 1988.Google Scholar
  107. 107.
    Feinberg E, Richardson DK, Als H, Sell E, Parad RB. Late pulmonary outcomes poorly predicted by early risk factors in very low birth weight infants. Pediatr Res 39:263A, 1997.Google Scholar
  108. 108.
    Escobedo MB, Hilliard JL, Smith F, et al. A baboon model of bronchopulmonary dysplasia: I. clinical features. Exp Mol Pathol 37:323–334, 1982.PubMedCrossRefGoogle Scholar
  109. 109.
    Coalson JJ, Kuehl TJ, Escobedo MB, et al. A baboon model of bronchopulmonary dysplasia: II. pathologic features. Exp Mol Pathol 37:335–350, 1982.PubMedCrossRefGoogle Scholar
  110. 110.
    Coalson JJ, Winter VT, Siler-Khodr T, Yoder BA. Neonatal chronic lung disease in extremely immature baboons. Am J Respir Crit Care Med 160:1333–1346, 1999.PubMedGoogle Scholar
  111. 111.
    Coalson JJ, Winter VT, Siler-Khodr T, Yoder BA. Neonatal chronic lung disease in extremely immature baboons. Am J Respir Crit Care Med 160:1333–1346, 1999.PubMedGoogle Scholar
  112. 112.
    Sunday ME, Yoder BA, Cuttitta F, Haley KJ, Emanuel RL. Bombesin-like peptide mediates lung injury in a baboon model of bronchopulmonary dysplasia. J Clin Invest 102:584–594, 1998.PubMedGoogle Scholar
  113. 113.
    Sunday ME, Yoder BA, Torday JS, Sikorski KA, Cuttitta F, Emanuel RL. Bombesin-like peptide (BLP) as a mediator of lung injury in two different baboon models of bronchopulmonary dysplasia. FASEB J 13(4):A1154 (abstract #857.4), 1999.Google Scholar
  114. 114.
    Subramaniam M, Sugiyama K, Coy D, Steiner C, Kong Y, Miller YE, Weller PF, Wada E, Sunday ME. Bombesin-like peptides and mast cell responses: relevance to bronchopulmonary dysplasia? Am J Respir Crit Care Med 168:601–611, 2003.PubMedCrossRefGoogle Scholar
  115. 115.
    Sheng H, Enghild JJ, Bowler R, et al. Effects of metalloporphyrin catalytic antioxidants in experimental brain ischemia. Free Radical Biol Med 33:947–961, 2002.CrossRefGoogle Scholar
  116. 116.
    Chang L, Subramaniam M, Yoder BA, et al. A catalytic antioxidant attenuates alveolar structural remodeling in bronchopulmonary dysplasia. Am J Respir Cell Mol Biol 167:57–64, 2003.Google Scholar
  117. 117.
    Groneck P, Gotze-Speer B, Oppermann M, Eiffert H, Speer CP. Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates. Pediatrics 93:712, 1994.PubMedGoogle Scholar
  118. 118.
    Lyle RE, Tryka AF, Griffin WS, Taylor BJ. Tryptase immunoreactive mast cell hyperplasia in bronchopulmonary dysplasia. Pediatr Pulmonol 19:336–343, 1995.PubMedCrossRefGoogle Scholar
  119. 119.
    Raghavender B, Smith JB. Eosinophil cationic protein in tracheal aspirates of preterm infants with bronchopulmonary dysplasia. J Pediatr 130:944–947, 1997.PubMedCrossRefGoogle Scholar
  120. 120.
    Gharaee-Kermani M, Phan SH. The role of eosinophils in pulmonary fibrosis. Int J Molec Med 1:43–53, 1998.PubMedGoogle Scholar
  121. 121.
    Pesci A, Bertorelli G, Gabrielli M, Olivieri D. Mast cells in fibrotic lung disorders. Chest 103:989–996, 1993.PubMedGoogle Scholar
  122. 122.
    Reiser KM, Last JA. Early cellular events in pulmonary fibrosis. Exp Lung Res 10:331–355, 1986.PubMedGoogle Scholar
  123. 123.
    Wasserman SL. The human lung mast cell. Env Health Persp 55:259–269, 1984.CrossRefGoogle Scholar
  124. 124.
    Ashour K, Sunday ME. Decreased alveolar development in fetal and newborn mice given bombesin. Pediatr Res 51(4)(Part 2 of 2):61A, Abstract 353, 2002.Google Scholar
  125. 125.
    Toti P, Buonocore G, Tanganelli P, et al. Bronchopulmonary dysplasia of the premature baby: an immunohistochemical study. Pediatr Pulmonol 24:22–28, 1997.PubMedCrossRefGoogle Scholar
  126. 126.
    Sun G, Stacey MA, Bellini A, Marini M, Mattoli S. Endothelin-1 induces bronchial myofibroblast differentiation. Peptides 18:1449–1451, 1997.PubMedCrossRefGoogle Scholar
  127. 127.
    Northway WH, Jr. Commentary. Bronchopulmonary dysplasia: twenty-five years later. Pediatr 89:969–973, 1992.Google Scholar
  128. 128.
    Zetter BR. Angiogenesis and tumor metastasis. Ann Rev Med 49:407–424, 1998.PubMedCrossRefGoogle Scholar
  129. 129.
    Beck L, D’Amore PA. Vascular development: cellular and molecular regulation. FASEB J 11:365–373, 1997.PubMedGoogle Scholar
  130. 130.
    Munshi UK, Niu JO, Siddiq MM, Parton LA. Elevation of interleukin-8 and interleukin-6 precedes the influx of neutrophils in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia. Pediatr Pulmonol 24:331–336, 1997.PubMedCrossRefGoogle Scholar
  131. 131.
    Brusselle GG, Kips JC, Tavernier JH, et al. Attenuation of allergic airway inflammation in IL-4 deficient mice. Clin Exp Allergy 24:73–80, 1994.PubMedCrossRefGoogle Scholar
  132. 132.
    Schwarze J, Cieslewicz G, Hamelmann E, et al. IL-5 and eosinophils are essential for the development of airway hyperresponsiveness following acute respiratory syncytial virus infection. J Immunol 162:2997–3004, 1999.PubMedGoogle Scholar
  133. 133.
    Viola JP, Kiani A, Bozza PT, Rao A. Regulation of allergic inflammation and eosinophil recruitment in mice lacking the transcription factor NFAT1: role of interleukin-4 (IL-4) and IL-5. Blood 91:2223–2230, 1998.PubMedGoogle Scholar
  134. 134.
    Matthaei KI, Foster P, Young IG. The role of interleukin-5 (IL-5) in vivo: studies with IL-5 deficient mice [Review]. Memorias do Instituto Oswaldo Cruz 92:63–68, 1997.PubMedGoogle Scholar
  135. 135.
    Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med 188:1307–1320, 1998.PubMedCrossRefGoogle Scholar
  136. 136.
    Mould AW, Ramsay AJ, Matthaei KI, Young IG, Rothenberg ME, Foster PS. The effect of IL-5 and eotaxin expression in the lung on eosinophil trafficking and degranulation and the induction of bronchial hyperreactivity. J Immunol 164:2142–2150, 2000.PubMedGoogle Scholar
  137. 137.
    Zhu Z, Homer RJ, Wang Z, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 103:779–788, 1999.PubMedGoogle Scholar
  138. 138.
    Lee JJ, McGarry MP, Farmer SC, et al. Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J Exp Med 185:2143–2156, 1997.PubMedCrossRefGoogle Scholar
  139. 139.
    Bozic CR, Lu B, Hopken UE, Gerard C, Gerard NP. Neurogenic amplification of immune complex inflammation. Science 273:1722–1725, 1996.PubMedCrossRefGoogle Scholar
  140. 140.
    Hopken UE, Lu B, Gerard NP, Gerard C. Impaired inflammation responses in the reverse Arthus reaction through genetic deletion of the C5a receptor. J Exp Med 186:749–756, 1997.PubMedCrossRefGoogle Scholar
  141. 141.
    Broide DH, Campbell K, Gifford T, Sriramarao P. Inhibition of eosinophilic inflammation in allergen-challenged, IL-1 receptor type 1-deficient mice is associated with reduced eosinophil rolling and adhesion on vascular endothelium. Blood 95:263–269, 2000.PubMedGoogle Scholar
  142. 142.
    Pryhuber GS, O’Brien DP, Baggs R, et al. Ablation of tumor necrosis factor receptor type 1 (p55) alters oxygen-induced lung injury. Am J Physiol Lung Cell Mol Physiol 278:L1082-L1090, 2000.PubMedGoogle Scholar
  143. 143.
    Ward NS, Waxman AB, Homer RJ, et al. Interleukin-6 induced protection in hyperoxic acute lung injury. Am J Respir Cell Mol Biol 22:535–542, 2000.PubMedGoogle Scholar
  144. 144.
    Yang X, Wang S, Fan Y, Han X. IL-10 deficiency prevents IL-5 overproduction and eosinophilic inflammation in a murine model of asthma-like reaction. Eur J Immunol 30:382–391, 2000.PubMedCrossRefGoogle Scholar
  145. 145.
    Waxman AB, Einarsson O, Seres T, et al. Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation. J Clin Invest 101:1970–1982, 1998.PubMedGoogle Scholar
  146. 146.
    Minamino T, Christou H, Hsieh C-M, et al. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia, 2001. Proc. Natl Acad Sci USA 98:8798–8803.PubMedCrossRefGoogle Scholar
  147. 147.
    Choi AMK, Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15:9–19, 1996.PubMedGoogle Scholar
  148. 148.
    Christou H, Morita T, Hsieh C-M, et al. Prevention of hypoxia-induced pulmonary hypertension by enhancement of endogenous heme oxygenase-1 in the rat. Circ Res 86:1224–1229, 2000.PubMedGoogle Scholar
  149. 149.
    Contreras M, Hariharan N, Lewandoski JR, Ciesielski W, Koscik R, Zimmerman JJ. Bronchoalveolar oxyradical inflammatory elements herald bronchopulmonary dysplasia. Crit Care Med 24:29–37, 1996.PubMedCrossRefGoogle Scholar
  150. 150.
    Parker RA, Lindstrom DP, Cotton RB. Evidence from twin study implies possible genetic susceptibility to bronchopulmonary dysplasia. Semin Perinatol 20:206–209, 1996.PubMedCrossRefGoogle Scholar
  151. 151.
    Evans M, Palta M, Sadek M, Weinstein MR, Peters ME. Associations between family history of asthma, bronchopulmonary dysplasia, and childhood asthma in very low birth weight children. Am J Epidemiol 148:460–466, 1998.PubMedGoogle Scholar
  152. 152.
    Nickerson BG, Taussig LM. Family history of asthma in infants with bronchopulmonary dysplasia. Pediatrics 65:1140–1144, 1980.PubMedGoogle Scholar
  153. 153.
    Weitzman M, Gortmaker S, Walker DK, Sobol A. Maternal smoking and childhood asthma. Pediatrics 85:505–511, 1990.PubMedGoogle Scholar
  154. 154.
    Martinez FD, Cline M, Burrows B. Increased incidence of asthma in children of smoking mothers. Pediatrics 89:21–26, 1992.PubMedGoogle Scholar
  155. 155.
    Hanrahan JP, Tager IB, Segal MR, et al. The effect of maternal smoking during pregnancy on early infant lung function. Am Rev Respir Dis 145:1129–1135, 1992.PubMedGoogle Scholar
  156. 156.
    Hoff C, Wertelecki W, BlackBurn WR, Mendenhall H, Wiseman H, Stumpe A. Trend associations of smoking with maternal, fetal and neonatal morbidity. Obstet Gynecol 68:317–321, 1986.PubMedGoogle Scholar
  157. 157.
    Chen MF, Kimizuka G, Wang NS. Human fetal lung changes associated with maternal smoking during pregnancy. Pediatr Pulmonol 3:51–58, 1987.PubMedCrossRefGoogle Scholar
  158. 158.
    Chen MF, Lewis SJ, Jagoe R, et al. Gastrin-releasing peptide gene products in mid-trimester human fetal lung with and without maternal smoking history during pregnancy. Pediatr Pulmonol 10:30–35, 1991.PubMedCrossRefGoogle Scholar
  159. 159.
    Huang M-H, Friend DS, Sunday ME, et al. An intrinsic adrenergic system in mammalian heart. J Clin Invest 98:1298–1303, 1996.PubMedCrossRefGoogle Scholar
  160. 160.
    Wuenschell CW, Sunday ME, Singh G, Minoo P, Slavkin HC, Warburton D. Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages. J Histochem Cytochem 44:113–123, 1996.PubMedGoogle Scholar
  161. 161.
    Lemaire I. Bombesin-related peptides modulate interleukin-1 production by alveolar macrophages. Neuropeptides 20:217–223, 1991.PubMedCrossRefGoogle Scholar
  162. 162.
    Lemaire I, Jones S, Khan MF. Bombesin-like peptides in alveolar macrophage: increased release in pulmonary inflammation and fibrosis. Neuropeptides 20:63–72, 1991.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  1. 1.Departments of PathologyBrigham & Women’s Hospital, Children’s Hospital, and Harvard Medical SchoolUSA

Personalised recommendations