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American Journal of Biomedical Research. 2013, 1(1), 13-24
DOI: 10.12691/ajbr-1-1-3
Open AccessReview Article

Molecular and Physiological Determinants of Pulmonary Developmental Biology: a Review

Asima Hameed1, 2, Muhammad Azhar Sherkheli1, , Abrar Hussain3 and Rizwan Ul-haq1

1Department of Pharmacy, Hazara University, Havelian Campus, Abbottabad, Pakistan

2Punjab Institute of Cardiology, Lahore, Pakistan

3Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan

Pub. Date: February 28, 2013

Cite this paper:
Asima Hameed, Muhammad Azhar Sherkheli, Abrar Hussain and Rizwan Ul-haq. Molecular and Physiological Determinants of Pulmonary Developmental Biology: a Review. American Journal of Biomedical Research. 2013; 1(1):13-24. doi: 10.12691/ajbr-1-1-3


The lungs undergo an extensive endodermal diverging morphogenesis along with alveogenesis, angiogenesis, and vasculogenesis to secure a sufficient diffusion surface for gaseous exchange. Any aberration in the course of normal development inculcating structural and functional abnormalities of lungs in antenatal life has potential morbidity in adult life. Factors such as IUGR, nutrient deficiency, FLM, Hypoxemia, ETS, surfactant deficiency, allergy and infections can adversely affect in-utero lungs development. Peculiar local and systemic inflammatory immune responses may elicit persistent architectural and physiological abnormalities. Lung surfactant produced by AEC-II cells is a mixture of phospholipids, surfactant proteins, and neutral lipids. Surfactant lowers alveolar surface tension, a crucial step for the prevention of alveolar collapse. Surfactant proteins are part of the innate immune defense of the lung. Surfactant deficiency and dysfunction is known to implicate a number of respiratory diseases especially allergic asthma and NRDS. The present article provides a state of the art review of the current knowledge of biology of normal lung development, its anatomical and molecular aspects, factors that regulate normal organogenesis of pulmonary system and molecular basis of respiratory allergic disorders including asthma.

respiratory diseases allergic disorders pulmonary development lung surfactants

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[1]  Warburton, D., et al., Lung organogenesis. Curr Top Dev Biol, 2010. 90: p. 73-158.
[2]  Greenough, A., Does low birth weight confer a lifelong respiratory disadvantage? Am J Respir Crit Care Med, 2009. 180(2): p. 107-8.
[3]  Harding, R., Sustained alterations in postnatal respiratory function following sub-optimal intrauterine conditions. Reprod Fertil Dev, 1995. 7(3): p. 431-41.
[4]  Barker, D.J.P., in Mothers, Babies, and Health in Later Life. 1998, Churchill Livingstone.
[5]  Jackson, B., et al., Examining the influence of early life socioeconomic position on pulmonary function across the life span: where do we go from here? Thorax, 2004. 59(3): p. 186-8.
[6]  Hanrahan, J.P., et al., The effect of maternal smoking during pregnancy on early infant lung function. Am Rev Respir Dis, 1992. 145(5): p. 1129-35.
[7]  Gern, J.E., Viral and bacterial infections in the development and progression of asthma. J Allergy Clin Immunol, 2000. 105(2 Pt 2): p. S497-502.
[8]  Gern, J.E., et al., Effects of viral respiratory infections on lung development and childhood asthma. J Allergy Clin Immunol, 2005. 115(4): p. 668-74; quiz 675.
[9]  Jackson, B., et al., A matter of life and breath: childhood socioeconomic status is related to young adult pulmonary function in the CARDIA study. Int J Epidemiol, 2004. 33(2): p. 271-8.
[10]  O'Connor, G.T., et al., The effect of passive smoking on pulmonary function and nonspecific bronchial responsiveness in a population-based sample of children and young adults. Am Rev Respir Dis, 1987. 135(4): p. 800-4.
[11]  Shaheen, S., The beginnings of chronic airflow obstruction. Br Med Bull, 1997. 53(1): p. 58-70.
[12]  Cliver, S.P., et al., The effect of cigarette smoking on neonatal anthropometric measurements. Obstet Gynecol, 1995. 85(4): p. 625-30.
[13]  Kotecha, S., Lung growth: implications for the newborn infant. Arch Dis Child Fetal Neonatal Ed, 2000. 82(1): p. F69-74.
[14]  Burri, P.H., Structural aspects of postnatal lung development - alveolar formation and growth. Biol Neonate, 2006. 89(4): p. 313-22.
[15]  Weibel ER, B.P.e., in The Lung: Scientific Foundations. 1997, Lipincott-Raven: Philadelphia.
[16]  Ten Have-Opbroek, A.A., The development of the lung in mammals: an analysis of concepts and findings. Am J Anat, 1981. 162(3): p. 201-19.
[17]  Ten Have-Opbroek, A.A., J.A. Dubbeldam, and C.J. Otto-Verberne, Ultrastructural features of type II alveolar epithelial cells in early embryonic mouse lung. Anat Rec, 1988. 221(4): p. 846-53.
[18]  Otto-Verberne, C.J. and A.A. Ten Have-Opbroek, Development of the pulmonary acinus in fetal rat lung: a study based on an antiserum recognizing surfactant-associated proteins. Anat Embryol (Berl), 1987. 175(3): p. 365-73.
[19]  Ten Have-Opbroek, A.A. and C.G. Plopper, Morphogenetic and functional activity of type II cells in early fetal rhesus monkey lungs. A comparison between primates and rodents. Anat Rec, 1992. 234(1): p. 93-104.
[20]  Langston, C., et al., Human lung growth in late gestation and in the neonate. Am Rev Respir Dis, 1984. 129(4): p. 607-13.
[21]  Thurlbeck, W.M., Postnatal human lung growth. Thorax, 1982. 37(8): p. 564-71.
[22]  Zorn, A.M. and J.M. Wells, Vertebrate endoderm development and organ formation. Annu Rev Cell Dev Biol, 2009. 25: p. 221-51.
[23]  Merkus, P.J., A.A. ten Have-Opbroek, and P.H. Quanjer, Human lung growth: a review. Pediatr Pulmonol, 1996. 21(6): p. 383-97.
[24]  Metzger, R.J., et al., The branching programme of mouse lung development. Nature, 2008. 453(7196): p. 745-50.
[25]  Wessells, N.K., Mammalian lung development: Interactions in formation and morphogenesis of tracheal buds. J. Exp. Zool, 1970. 175(4): p. 455-466.
[26]  Spooner, B.S. and N.K. Wessells, Mammalian lung development: interactions in primordium formation and bronchial morphogenesis. J Exp Zool, 1970. 175(4): p. 445-54.
[27]  Post, M., Tissue interactions, in The Lung: Scientific Foundations, W.J. Crystal RG, Barnes PJ,, Editor. 1997, Raven Press: New York. p. 1003-1010.
[28]  Warburton, D., et al., Molecular embryology and the study of lung development. Am J Respir Cell Mol Biol, 1993. 9(1): p. 5-9.
[29]  Thurlbeck, W.M., Postnatal growth and development of the lung. Am Rev Respir Dis, 1975. 111(6): p. 803-44.
[30]  Adamson, I.Y. and G.M. King, Epithelial-mesenchymal interactions in postnatal rat lung growth. Exp Lung Res, 1985. 8(4): p. 261-74.
[31]  Spooner, B.S. and J.M. Faubion, Collagen involvement in branching morphogenesis of embryonic lung and salivary gland. Dev Biol, 1980. 77(1): p. 84-102.
[32]  Larson, J.E., Developmental control of collagen gene expression in the rat lung: confirmation of early observations of lung growth. Pediatr Pulmonol, 1993. 15(4): p. 205-8.
[33]  Burri, P.H., Lung development and pulmonary angiogenesis, in Lung Development, B.J. Gaulter C, Post M, Editor. 1999, Oxford University Press: New York. p. 122-151.
[34]  Hislop, A.A., Fetal and postnatal anatomical lung development, in Neonatal Respiratory Disorders, A.a.M. Greenough, AD,, Editor. 2003, Arnold:: London. p. 3-11.
[35]  Thurlbeck, W.M., Pre-and postnatal organ development, in Basic mechanisms of respiratory disease: Cellular and integrative, M.R. Chernick J, Editor. 1991, BC Decker: Philadelphia. p. 23-35.
[36]  Adamson, I., Development of lung structure, in The Lung: Scientific Foundations, W.J. Crystal RG, Barnes PJ, Editor. 1991, Raven Press: New York. p. 993-1001.
[37]  Hilfer, S.R., Morphogenesis of the lung: control of embryonic and fetal branching. Annu Rev Physiol, 1996. 58: p. 93-113.
[38]  Keeling, J., T.Y. Khong, and S. Gould, The Respiratory System, in Fetal and Neonatal Pathology. 2007, Springer London. p. 531-570.
[39]  McDougall, J. and J.F. Smith, The development of the human type II pneumocyte. J Pathol, 1975. 115(4): p. 245-51.
[40]  MacDonald, J., Lung growth and development. . Vol. 13. 1997, New York: Marcel Decker.
[41]  Warburton, D., et al., The molecular basis of lung morphogenesis. Mech Dev, 2000. 92(1): p. 55-81.
[42]  Olver, R.E. and L.B. Strang, Ion fluxes across the pulmonary epithelium and the secretion of lung liquid in the foetal lamb. J Physiol, 1974. 241(2): p. 327-57.
[43]  Brown, M.J., et al., Effects of adrenaline and of spontaneous labour on the secretion and absorption of lung liquid in the fetal lamb. J Physiol, 1983. 344: p. 137-52.
[44]  Frank, L. and I.R. Sosenko, Failure of premature rabbits to increase antioxidant enzymes during hyperoxic exposure: increased susceptibility to pulmonary oxygen toxicity compared with term rabbits. Pediatr Res, 1991. 29(3): p. 292-6.
[45]  Maeda, Y., V. Dave, and J.A. Whitsett, Transcriptional control of lung morphogenesis. Physiol Rev, 2007. 87(1): p. 219-44.
[46]  Zorn, A.M. and J.M. Wells, Molecular basis of vertebrate endoderm development. Int Rev Cytol, 2007. 259: p. 49-111.
[47]  Morrisey, E.E. and B.L. Hogan, Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell, 2010. 18(1): p. 8-23.
[48]  Gang Chen, H.W., Fengming Luo, Liqian Zhang, Yan Xu, and M.W.-K. Ian Lewkowich, and Jeffrey A. Whitsett, Foxa2 Programs Th2 Cell-Mediated Innate Immunity in the Developing Lung. The Journal of Immunology, 2010. 184: p. 6133-6141.
[49]  Chen, F., et al., Inhibition of Tgf beta signaling by endogenous retinoic acid is essential for primary lung bud induction. Development, 2007. 134(16): p. 2969-79.
[50]  Cardoso, W.V. and J. Lu, Regulation of early lung morphogenesis: questions, facts and controversies. Development, 2006. 133(9): p. 1611-24.
[51]  Mailleux, A.A., et al., Evidence that SPROUTY2 functions as an inhibitor of mouse embryonic lung growth and morphogenesis. Mech Dev, 2001. 102(1-2): p. 81-94.
[52]  Bostrom, H., et al., PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell, 1996. 85(6): p. 863-73.
[53]  Weinstein, M., et al., FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. Development, 1998. 125(18): p. 3615-23.
[54]  Shannon, J.M. and B.A. Hyatt, Epithelial-mesenchymal interactions in the developing lung. Annu Rev Physiol, 2004. 66: p. 625-45.
[55]  Flamme, I., G. Breier, and W. Risau, Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (flk-1) are expressed during vasculogenesis and vascular differentiation in the quail embryo. Dev Biol, 1995. 169(2): p. 699-712.
[56]  Flamme, I., et al., Overexpression of vascular endothelial growth factor in the avian embryo induces hypervascularization and increased vascular permeability without alterations of embryonic pattern formation. Dev Biol, 1995. 171(2): p. 399-414.
[57]  Gebb, S.A. and J.M. Shannon, Tissue interactions mediate early events in pulmonary vasculogenesis. Dev Dyn, 2000. 217(2): p. 159-69.
[58]  Yamaguchi, T.P., et al., flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial cell precursors. Development, 1993. 118(2): p. 489-98.
[59]  Drake, C.J. and C.D. Little, Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization. Proc Natl Acad Sci U S A, 1995. 92(17): p. 7657-61.
[60]  Baldwin, H.S., Early embryonic vascular development. Cardiovasc Res, 1996. 31 Spec No: p. E34-45.
[61]  Zhao, L., et al., Vascular endothelial growth factor co-ordinates proper development of lung epithelium and vasculature. Mech Dev, 2005. 122(7-8): p. 877-86.
[62]  Schittny, J.C., et al., Programmed cell death contributes to postnatal lung development. Am J Respir Cell Mol Biol, 1998. 18(6): p. 786-93.
[63]  Sasaki, H. and B.L. Hogan, HNF-3 beta as a regulator of floor plate development. Cell, 1994. 76(1): p. 103-15.
[64]  Thebaud, B., Update in Pediatric Lung Disease. Am J Respir Crit Care Med, 2011. 183: p. 1477-1481.
[65]  Attar, M.A. and S. Sarkar, Developmental Lung Anomalies, in Manual of Neonatal Respiratory Care, S.M. Donn and S.K. Sinha, Editors. 2012, Springer. p. 17.
[66]  Gabbi Parker, H.V., Management of upper airway obstruction in children. Paediatrics and Child Health, 2009. 19(6): p. 276-281.
[67]  Maritz, G.S., C.J. Morley, and R. Harding, Early developmental origins of impaired lung structure and function. Early Human Development, 2005. 81(9): p. 763-771.
[68]  Groenman, F., S. Unger, and M. Post, The molecular basis for abnormal human lung development. Neonatology, 2005. 87(3): p. 164-177.
[69]  Kassner, E.G., et al., Pulmonary candidiasis in infants: clinical, radiologic, and pathologic features. AJR Am J Roentgenol, 1981. 137(4): p. 707-16.
[70]  Keller, M.A., et al., Systemic candidiasis in infants: a case presentation and literature review. Am J Dis Child, 1977. 131(11): p. 1260-3.
[71]  Gravett, M.G., et al., Independent associations of bacterial vaginosis and Chlamydia trachomatis infection with adverse pregnancy outcome. JAMA, 1986. 256(14): p. 1899-903.
[72]  Lamont, R.F., et al., The role of mycoplasmas, ureaplasmas and chlamydiae in the genital tract of women presenting in spontaneous early preterm labour. J Med Microbiol, 1987. 24(3): p. 253-7.
[73]  Cassell, G.H., et al., Ureaplasma urealyticum intrauterine infection: role in prematurity and disease in newborns. Clin Microbiol Rev, 1993. 6(1): p. 69-87.
[74]  Modlin, J.F., Perinatal echovirus infection: insights from a literature review of 61 cases of serious infection and 16 outbreaks in nurseries. Rev Infect Dis, 1986. 8(6): p. 918-26.
[75]  Abzug, M.J., et al., Viral pneumonia in the first month of life. Pediatr Infect Dis J, 1990. 9(12): p. 881-5.
[76]  Northway, W.H., Jr., R.C. Rosan, and D.Y. Porter, Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med, 1967. 276(7): p. 357-68.
[77]  Jobe, A.H., Antenatal factors and the development of bronchopulmonary dysplasia. Semin Neonatol, 2003. 8(1): p. 9-17.
[78]  Jobe, A.H. and E. Bancalari, Bronchopulmonary dysplasia. Am J Respir Crit Care Med, 2001. 163(7): p. 1723-9.
[79]  Harding, R., et al., The compromised intra-uterine environment: implications for future lung health. Clin Exp Pharmacol Physiol, 2000. 27(12): p. 965-74.
[80]  Hooper, S.B. and R. Harding, Fetal lung liquid: a major determinant of the growth and functional development of the fetal lung. Clin Exp Pharmacol Physiol, 1995. 22(4): p. 235-47.
[81]  Wilson, S.M., R.E. Olver, and D.V. Walters, Developmental regulation of lumenal lung fluid and electrolyte transport. Respir Physiol Neurobiol, 2007. 159(3): p. 247-55.
[82]  Alcorn, D., et al., Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung. J Anat, 1977. 123(Pt 3): p. 649-60.
[83]  Moessinger, A.C., et al., Role of lung fluid volume in growth and maturation of the fetal sheep lung. J Clin Invest, 1990. 86(4): p. 1270-7.
[84]  Wigglesworth, J.S. and R. Desai, Is fetal respiratory function a major determinant of perinatal survival? Lancet, 1982. 1(8266): p. 264-7.
[85]  Sahebjami, H., Nutrition and lung structure and function. Exp Lung Res, 1993. 19(2): p. 105-24.
[86]  Kalenga M, G.C., Burri P. H, Nutritional aspects of lung development., in Lung Development, B.J. Gaultier C, Post M, Editor. 1999, Oxford University Press: New York. p. 347-63.
[87]  Curle, D.C. and I.Y. Adamson, Retarded development of noenatal rat lung by maternal malnutrition. J Histochem Cytochem, 1978. 26(5): p. 401-8.
[88]  Lin, Y. and A.J. Lechner, Surfactant content and type II cell development in fetal guinea pig lungs during prenatal starvation. Pediatr Res, 1991. 29(3): p. 288-91.
[89]  Faridy, E.E., Effect of maternal malnutrition on surface activity of fetal lungs in rats. J Appl Physiol, 1975. 39(4): p. 535-40.
[90]  Winick, M. and A. Noble, Cellular response in rats during malnutrition at various ages. J Nutr, 1966. 89(3): p. 300-6.
[91]  Sahebjami, H. and J. MacGee, Effects of starvation on lung mechanics and biochemistry in young and old rats. J Appl Physiol, 1985. 58(3): p. 778-84.
[92]  Das, R.M., The effects of intermittent starvation on lung development in suckling rats. Am J Pathol, 1984. 117(2): p. 326-32.
[93]  Liu, M., A.K. Tanswell, and M. Post, Mechanical force-induced signal transduction in lung cells. Am J Physiol, 1999. 277(4 Pt 1): p. L667-83.
[94]  Lechner, A.J., D.C. Winston, and J.E. Bauman, Lung mechanics, cellularity, and surfactant after prenatal starvation in guinea pigs. J Appl Physiol, 1986. 60(5): p. 1610-4.
[95]  Massaro, D., et al., Postnatal development of alveoli. Regulation and evidence for a critical period in rats. J Clin Invest, 1985. 76(4): p. 1297-305.
[96]  Bellanti, J.A., B.J. Zeligs, and L.L. Kulszycki, Nutrition and development of pulmonary defense mechanisms. Pediatr Pulmonol Suppl, 1997. 16: p. 170-1.
[97]  Morsing, E., P. Gustafsson, and J. Brodszki, Lung function in children born after foetal growth restriction and very preterm birth. Acta Paediatr, 2012. 101(1): p. 48-54.
[98]  Larson, J.E. and W.M. Thurlbeck, The effect of experimental maternal hypoxia on fetal lung growth. Pediatr Res, 1988. 24(2): p. 156-9.
[99]  Jacobs, R., et al., The effect of prolonged hypobaric hypoxia on growth of fetal sheep. J Dev Physiol, 1988. 10(2): p. 97-112.
[100]  Gortner, L., et al., Hypoxia-induced intrauterine growth retardation: effects on pulmonary development and surfactant protein transcription. Biol Neonate, 2005. 88(2): p. 129-35.
[101]  Prabhakar, N.R. and G.L. Semenza, Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2. Physiological Reviews, 2012. 92(3): p. 967-1003.
[102]  Groenman, F., et al., Hypoxia-inducible factors in the first trimester human lung. Journal of Histochemistry & Cytochemistry, 2007. 55(4): p. 355-363.
[103]  Patel, S.A. and M.C. Simon, Biology of hypoxia-inducible factor-2α in development and disease. Cell Death & Differentiation, 2008. 15(4): p. 628-634.
[104]  Boland, R., et al., Cortisol enhances structural maturation of the hypoplastic fetal lung in sheep. J Physiol, 2004. 554(Pt 2): p. 505-17.
[105]  Jones, M.B., Respiratory distress syndrome and the induction of fetal lung maturity by the use of glucocorticoids. JOGN Nurs, 1977. 6(4): p. 21-8.
[106]  Riley, C.A., K. Boozer, and T.L. King, Antenatal corticosteroids at the beginning of the 21st century. J Midwifery Womens Health, 2011. 56(6): p. 591-7.
[107]  Holsapple, M.P., L.J. West, and K.S. Landreth, Species comparison of anatomical and functional immune system development. Birth Defects Res B Dev Reprod Toxicol, 2003. 68(4): p. 321-34.
[108]  Rona, R.J., M.C. Gulliford, and S. Chinn, Effects of prematurity and intrauterine growth on respiratory health and lung function in childhood. BMJ, 1993. 306(6881): p. 817-20.
[109]  Wapner, R. and A.H. Jobe, Controversy: Antenatal Steroids. Clinics in Perinatology, 2011. 38(3): p. 529-545.
[110]  Lambrecht, B.N. and H. Hammad, Biology of lung dendritic cells at the origin of asthma. Immunity, 2009. 31(3): p. 412-24.
[111]  Leibnitz, R., Development of the human immune system, in Developmental immunotoxicology, H. SD., Editor. 2005, CRC Press: Boca Raton. p. 21-42.
[112]  Abraham, C.M. and D.R. Ownby, Ontogeny of the allergic inflammatory response. Immunol Allergy Clin North Am, 2005. 25(2): p. 215-29, v.
[113]  Holt, P.G., J.W. Upham, and P.D. Sly, Contemporaneous maturation of immunologic and respiratory functions during early childhood: implications for development of asthma prevention strategies. J Allergy Clin Immunol, 2005. 116(1): p. 16-24; quiz 25.
[114]  Diamond, G., D. Legarda, and L.K. Ryan, The innate immune response of the respiratory epithelium. Immunol Rev, 2000. 173: p. 27-38.
[115]  Schulz, C., et al., Differences in LPS-induced activation of bronchial epithelial cells (BEAS-2B) and type II-like pneumocytes (A-549). Scand J Immunol, 2002. 56(3): p. 294-302.
[116]  Hou, Y.F., et al., Modulation of expression and function of Toll-like receptor 3 in A549 and H292 cells by histamine. Mol Immunol, 2006. 43(12): p. 1982-92.
[117]  Hewson, C.A., et al., Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells. J Virol, 2005. 79(19): p. 12273-9.
[118]  Vogt-Eisele, A.K., et al., Monoterpenoid agonists of TRPV3. Br J Pharmacol, 2007. 151(4): p. 530-40.
[119]  Sherkheli, M.A., et al., Characterization of selective TRPM8 ligands and their structure activity response (S.A.R) relationship. J Pharm Pharm Sci, 2010. 13(2): p. 242-53.
[120]  Sherkheli, M.A., et al., Monoterpenoids induce agonist-specific desensitization of transient receptor potential vanilloid-3 (TRPV3) ion channels. J Pharm Pharm Sci, 2009. 12(1): p. 116-28.
[121]  Sherkheli, M.A., et al., Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. Pak J Pharm Sci, 2008. 21(4): p. 370-8.
[122]  Sherkheli, M.A., Gisselmann G. and Hatt H., Supercooling Agent Icilin Blocks a Warmth-Sensing Ion Channel TRPV3. The Scientific World Journal, 2012. 2012.
[123]  Preti, D., A. Szallasi, and R. Patacchini, TRP channels as therapeutic targets in airway disorders: a patent review. Expert Opin Ther Pat, 2012. 22(6): p. 663-95.
[124]  Gosling, M., C. Poll, and S. Li, TRP channels in airway smooth muscle as therapeutic targets. Naunyn Schmiedebergs Arch Pharmacol, 2005. 371(4): p. 277-84.
[125]  Sha, Q., et al., Activation of airway epithelial cells by toll-like receptor agonists. Am J Respir Cell Mol Biol, 2004. 31(3): p. 358-64.
[126]  Muir, A., et al., Toll-like receptors in normal and cystic fibrosis airway epithelial cells. Am J Respir Cell Mol Biol, 2004. 30(6): p. 777-83.
[127]  127.Oshikawa, K. and Y. Sugiyama, Regulation of toll-like receptor 2 and 4 gene expression in murine alveolar macrophages. Exp Lung Res, 2003. 29(6): p. 401-12.
[128]  Holt, P.G., Programming for responsiveness to environmental antigens that trigger allergic respiratory disease in adulthood is initiated during the perinatal period. Environ Health Perspect, 1998. 106 Suppl 3: p. 795-800.
[129]  Reynolds, H.Y., Lung inflammation and fibrosis: an alveolar macrophage-centered perspective from the 1970s to 1980s. Am J Respir Crit Care Med, 2005. 171(2): p. 98-102.
[130]  Fels, A.O. and Z.A. Cohn, The alveolar macrophage. J Appl Physiol, 1986. 60(2): p. 353-69.
[131]  Mosmann, T.R. and S. Sad, The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today, 1996. 17(3): p. 138-46.
[132]  Robinson, D.S., et al., Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med, 1992. 326(5): p. 298-304.
[133]  Devereux, G., R.N. Barker, and A. Seaton, Antenatal determinants of neonatal immune responses to allergens. Clin Exp Allergy, 2002. 32(1): p. 43-50.
[134]  Devereux, G., A. Seaton, and R.N. Barker, In utero priming of allergen-specific helper T cells. Clin Exp Allergy, 2001. 31(11): p. 1686-95.
[135]  Liao, S.Y., et al., Decreased production of IFN gamma and increased production of IL-6 by cord blood mononuclear cells of newborns with a high risk of allergy. Clin Exp Allergy, 1996. 26(4): p. 397-405.
[136]  Miles, E.A., et al., Peripheral blood mononuclear cell proliferative responses in the first year of life in babies born to allergic parents. Clin Exp Allergy, 1996. 26(7): p. 780-8.
[137]  Prescott, S.L., et al., Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol, 1998. 160(10): p. 4730-7.
[138]  Tang, M.L., et al., Reduced interferon-gamma secretion in neonates and subsequent atopy. Lancet, 1994. 344(8928): p. 983-5.
[139]  Gold, D.R. and R. Wright, Population disparities in asthma. Annu Rev Public Health, 2005. 26: p. 89-113.
[140]  Pinkerton, K.E. and J.P. Joad, Influence of air pollution on respiratory health during perinatal development. Clin Exp Pharmacol Physiol, 2006. 33(3): p. 269-72.
[141]  Sly, R.M., Changing prevalence of allergic rhinitis and asthma. Ann Allergy Asthma Immunol, 1999. 82(3): p. 233-48; quiz 248-52.
[142]  Hamada, K., et al., Exposure of pregnant mice to an air pollutant aerosol increases asthma susceptibility in offspring. J Toxicol Environ Health A, 2007. 70(8): p. 688-95.
[143]  Jones, C.A., J.A. Holloway, and J.O. Warner, Fetal immune responsiveness and routes of allergic sensitization. Pediatr Allergy Immunol, 2002. 13 Suppl 15: p. 19-22.
[144]  Pattle, R.E., Properties, function and origin of the alveolar lining layer. Nature, 1955. 175(4469): p. 1125-6.
[145]  Szekers-Bartho, J., Immunological Relationship between the Mother and the Fetus. International Reviews of Immunology, 2002. 21(6): p. 471-495.
[146]  Warner, J.A., et al., Prenatal origins of allergic disease. J Allergy Clin Immunol, 2000. 105(2 Pt 2): p. S493-8.
[147]  Gon, Y., et al., A20 inhibits toll-like receptor 2- and 4-mediated interleukin-8 synthesis in airway epithelial cells. Am J Respir Cell Mol Biol, 2004. 31(3): p. 330-6.
[148]  Holgate, S.T., The epithelium takes centre stage in asthma and atopic dermatitis. Trends Immunol, 2007. 28(6): p. 248-51.
[149]  Kuroki, Y. and D.R. Voelker, Pulmonary surfactant proteins. J Biol Chem, 1994. 269(42): p. 25943-6.
[150]  Frerking, I., et al., Pulmonary surfactant: functions, abnormalities and therapeutic options. Intensive Care Med, 2001. 27(11): p. 1699-717.
[151]  Griese, M., Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J, 1999. 13(6): p. 1455-76.
[152]  Wright, J.R., Clearance and recycling of pulmonary surfactant. Am J Physiol, 1990. 259(2 Pt 1): p. L1-12.
[153]  Field, N.T. and W.M. Gilbert, Current status of amniotic fluid tests of fetal maturity. Clin Obstet Gynecol, 1997. 40(2): p. 366-86.
[154]  Bernhard, W., et al., Phosphatidylcholine molecular species in lung surfactant: composition in relation to respiratory rate and lung development. Am J Respir Cell Mol Biol, 2001. 25(6): p. 725-31.
[155]  Tokieda, K., et al., Pulmonary dysfunction in neonatal SP-B-deficient mice. Am J Physiol, 1997. 273(4 Pt 1): p. L875-82.
[156]  Whitsett, J.A., Review: The intersection of surfactant homeostasis and innate host defense of the lung: lessons from newborn infants. Innate Immunity, 2010. 16(3): p. 138-142.
[157]  Izzo, C. and P.P. Rickham, Neonatal pulmonary hamartoma. Journal of Pediatric Surgery, 1968. 3(1, Part 1): p. 77-83.
[158]  Hobo, S., et al., Effect of transportation on the composition of bronchoalveolar lavage fluid obtained from horses. Am J Vet Res, 1997. 58(5): p. 531-4.
[159]  Hobo, S., et al., Surfactant proteins in bronchoalveolar lavage fluid of horses: assay technique and changes following road transport. Vet Rec, 2001. 148(3): p. 74-80.
[160]  Ito, S., S. Hobo, and Y. Kasashima, Bronchoalveolar lavage fluid findings in the atelectatic regions of anesthetized horses. J Vet Med Sci, 2003. 65(9): p. 1011-3.
[161]  Morrison, K.E., et al., Functional and compositional changes in pulmonary surfactant in response to exercise. Equine Vet J Suppl, 1999. 30: p. 62-6.
[162]  Danlois, F., et al., Pulmonary surfactant from healthy Belgian White and Blue and Holstein Friesian calves: biochemical and biophysical comparison. Vet J, 2003. 165(1): p. 65-72.
[163]  Christmann, U., et al., Abnormalities in lung surfactant in horses clinically affected with recurrent airway obstruction (RAO). J Vet Intern Med, 2008. 22(6): p. 1452-5.
[164]  Danlois, F., et al., Very low surfactant protein C contents in newborn Belgian White and Blue calves with respiratory distress syndrome. Biochem J, 2000. 351 Pt 3: p. 779-87.
[165]  Bernhard, W., et al., Conductive airway surfactant: surface-tension function, biochemical composition, and possible alveolar origin. Am J Respir Cell Mol Biol, 1997. 17(1): p. 41-50.
[166]  Wright, J.R., Immunoregulatory functions of surfactant proteins. Nat Rev Immunol, 2005. 5(1): p. 58-68.
[167]  Weaver, T.E. and J.J. Conkright, Function of surfactant proteins B and C. Annu Rev Physiol, 2001. 63: p. 555-78.
[168]  Whitsett, J.A. and T.E. Weaver, Hydrophobic surfactant proteins in lung function and disease. N Engl J Med, 2002. 347(26): p. 2141-8.
[169]  Madsen, J., et al., Localization of lung surfactant protein D on mucosal surfaces in human tissues. J Immunol, 2000. 164(11): p. 5866-70.
[170]  Leth-Larsen, R., et al., Surfactant protein D in the female genital tract. Mol Hum Reprod, 2004. 10(3): p. 149-54.
[171]  Rau, G.A., et al., Surfactant in newborn compared with adolescent pigs: adaptation to neonatal respiration. Am J Respir Cell Mol Biol, 2004. 30(5): p. 694-701.
[172]  Sano, H. and Y. Kuroki, The lung collectins, SP-A and SP-D, modulate pulmonary innate immunity. Mol Immunol, 2005. 42(3): p. 279-87.
[173]  Macklem, P.T., D.F. Proctor, and J.C. Hogg, The stability of peripheral airways. Respir Physiol, 1970. 8(2): p. 191-203.
[174]  Notter, R.H., Lung surfactants: basic science and clinical applications, in Lung Biology in Health and Disease, C. L, Editor. 2000, Dekker: New York. p. 207-248.
[175]  Enhorning, G., L.C. Duffy, and R.C. Welliver, Pulmonary surfactant maintains patency of conducting airways in the rat. Am J Respir Crit Care Med, 1995. 151(2 Pt 1): p. 554-6.
[176]  Meyer, K.C. and J.J. Zimmerman, Inflammation and surfactant. Paediatr Respir Rev, 2002. 3(4): p. 308-14.
[177]  Wright, J.R., Host defense functions of pulmonary surfactant. Biol Neonate, 2004. 85(4): p. 326-32.
[178]  Wright, J.R., Pulmonary surfactant: a front line of lung host defense. J Clin Invest, 2003. 111(10): p. 1453-5.
[179]  Chiba, H., et al., Human surfactant protein D (SP-D) binds Mycoplasma pneumoniae by high affinity interactions with lipids. Journal of Biological Chemistry, 2002. 277(23): p. 20379-20385.
[180]  Reidy, M.F. and J.R. Wright, Surfactant protein A enhances apoptotic cell uptake and TGF-beta1 release by inflammatory alveolar macrophages. American journal of physiology. Lung cellular and molecular physiology, 2003. 285(4): p. L854-61.
[181]  Matalon, S. and J.R. Wright, Surfactant proteins and inflammation: the yin and the yang. Am J Respir Cell Mol Biol, 2004. 31(6): p. 585-6.
[182]  De Sanctis, G.T., et al., Exogenous surfactant enhances mucociliary clearance in the anaesthetized dog. Eur Respir J, 1994. 7(9): p. 1616-21.
[183]  Baritussio, A., Lung surfactant, asthma, and allergens: a story in evolution. Am J Respir Crit Care Med, 2004. 169(5): p. 550-1.
[184]  Annamari Salminen, R.V., Reija Paananen, Marja Ojaniemi, Mikko Hallman, Surfactant protein D modulates levels of IL-10 and TNF-α in intrauterine compartments during lipopolysaccharide-induced preterm birth. Cytokine, 2012. 60(2): p. 423-430.
[185]  Annamari Salminen, R.V., Reija Paananen, Marja Ojaniemi, Mikko Hallman, Surfactant protein A modulates the lipopolysaccharide-induced inflammatory response related to preterm birth. Cytokine 2011. 56(2): p. 442-449.
[186]  King, B.A. and K. Paul S, Surfactant Protein D Deficiency Increases Lung Injury During Endotoxemia. Am J Respir Cell Mol Biol, 2011. 44: p. 709-715.
[187]  Wilsher, M.L., D.A. Hughes, and P.L. Haslam, Immunoregulatory properties of pulmonary surfactant: effect of lung lining fluid on proliferation of human blood lymphocytes. Thorax, 1988. 43(5): p. 354-9.
[188]  Chao, W., R.G. Spragg, and R.M. Smith, Inhibitory effect of porcine surfactant on the respiratory burst oxidase in human neutrophils. Attenuation of p47phox and p67phox membrane translocation as the mechanism. J Clin Invest, 1995. 96(6): p. 2654-60.
[189]  Wu, Y.Z., et al., Surfactant protein-A and phosphatidylglycerol suppress type IIA phospholipase A2 synthesis via nuclear factor-kappaB. Am J Respir Crit Care Med, 2003. 168(6): p. 692-9.
[190]  Hirche, T.O., et al., Neutrophil serine proteinases inactivate surfactant protein D by cleaving within a conserved subregion of the carbohydrate recognition domain. J Biol Chem, 2004. 279(26): p. 27688-98.
[191]  Ackerman, S.J., et al., Hydrolysis of surfactant phospholipids catalyzed by phospholipase A2 and eosinophil lysophospholipases causes surfactant dysfunction: a mechanism for small airway closure in asthma. Chest, 2003. 123(3 Suppl): p. 355S.
[192]  Seeds, M.C., et al., Human eosinophil group IID secretory phospholipase A2 causes surfactant dysfunction. Chest, 2003. 123(3 Suppl): p. 376S-7S.
[193]  McSharry, C., et al., Takes your breath away--the immunology of allergic alveolitis. Clin Exp Immunol, 2002. 128(1): p. 3-9.
[194]  Hesselmar, B., et al., Asthma in children: prevalence, treatment, and sensitization. Pediatric allergy and immunology, 2002. 11(2): p. 74-79.
[195]  Masoli, M., et al., The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy, 2004. 59(5): p. 469-78.
[196]  Brusasco, V. and R. Pellegrino, Complexity of factors modulating airway narrowing in vivo: relevance to assessment of airway hyperresponsiveness. J Appl Physiol, 2003. 95(3): p. 1305-13.
[197]  James, A., Airway remodeling in asthma. Curr Opin Pulm Med, 2005. 11(1): p. 1-6.
[198]  Sears, M.R., Lung function decline in asthma. Eur Respir J, 2007. 30(3): p. 411-3.
[199]  Kurashima, K., et al., Surface activity of sputum from acute asthmatic patients. Am J Respir Crit Care Med, 1997. 155(4): p. 1254-9.
[200]  Jarjour, N.N. and G. Enhorning, Antigen-induced airway inflammation in atopic subjects generates dysfunction of pulmonary surfactant. Am J Respir Crit Care Med, 1999. 160(1): p. 336-41.
[201]  Hohlfeld, J.M., et al., Eosinophil cationic protein alters pulmonary surfactant structure and function in asthma. J Allergy Clin Immunol, 2004. 113(3): p. 496-502.
[202]  Singh, M., Infection and Allergy: The Inverse Link. Asthma in Children, 2012: p. 38.
[203]  Hohlfeld, J.M., et al., Dysfunction of pulmonary surfactant in asthmatics after segmental allergen challenge. Am J Respir Crit Care Med, 1999. 159(6): p. 1803-9.
[204]  Heeley, E.L., et al., Phospholipid molecular species of bronchoalveolar lavage fluid after local allergen challenge in asthma. Am J Physiol Lung Cell Mol Physiol, 2000. 278(2): p. L305-11.
[205]  Wright, S.M., et al., Altered airway surfactant phospholipid composition and reduced lung function in asthma. J Appl Physiol, 2000. 89(4): p. 1283-92.
[206]  Hite, R.D., et al., Surfactant phospholipid changes after antigen challenge: a role for phosphatidylglycerol in dysfunction. Am J Physiol Lung Cell Mol Physiol, 2005. 288(4): p. L610-7.
[207]  Pohunek, P., et al., Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma. Pediatr Allergy Immunol, 2005. 16(1): p. 43-51.
[208]  Hite, R.D., et al., Lysophospholipid generation and phosphatidylglycerol depletion in phospholipase A(2)-mediated surfactant dysfunction. Am J Physiol Lung Cell Mol Physiol, 2005. 288(4): p. L618-24.
[209]  Van Den Toorn, L.M., et al., Airway inflammation is present during clinical remission of atopic asthma. American journal of respiratory and critical care medicine, 2001. 164(11): p. 2107-2113.
[210]  Henderson, A.J. and J.O. Warner. Fetal origins of asthma. in Seminars in Fetal and Neonatal Medicine. 2012: Elsevier.
[211]  Babu, K.S., et al., Inhaled synthetic surfactant abolishes the early allergen-induced response in asthma. Eur Respir J, 2003. 21(6): p. 1046-9.
[212]  Kurashima, K., et al., A pilot study of surfactant inhalation in the treatment of asthmatic attack. Arerugi, 1991. 40(2): p. 160-3.
[213]  Fujiwara, T., et al., Artificial surfactant therapy in hyaline-membrane disease. Lancet, 1980. 1(8159): p. 55-9.
[214]  Jobe, A.H., Pulmonary surfactant therapy. N Engl J Med, 1993. 328(12): p. 861-8.
[215]  Anand, D., et al., Lung function and respiratory health in adolescents of very low birth weight. Arch Dis Child, 2003. 88(2): p. 135-8.
[216]  Bersani, I., C.P. Speer, and S. Kunzmann, Surfactant proteins A and D in pulmonary diseases of preterm infants. Expert Review of Anti-infective Therapy, 2012. 10(5): p. 573-584.
[217]  Vyas, J. and S. Kotecha, Effects of antenatal and postnatal corticosteroids on the preterm lung. Arch Dis Child Fetal Neonatal Ed, 1997. 77(2): p. F147-50.