Susan H Guttentag, M.D.

Faculty Appointments
Professor of Pediatrics Julia Carell Stadler Chair in Pediatrics
M.D., Medical College of Pennsylvania, Philadelphia, PennsylvaniaB.A., University of Pennsylvania, Philadelphia, Pennsylvania
Office Address
Division of Neonatology
11111 Doctor's Office Tower
2200 Children's Way
Nashville, TN
Research Description
I am a phyician-scientist with experience in clinical neonatology, and research interest in newborn lung disease. Lung surfactant plays an important role in managing both premature and term newborns with lung disease. Surfactant is a soapy material made by cells in the small airspaces of the lung, the alveolar type 2 cells, to maintain inflation of airspaces during the breathing cycle. Diseases of surfactant fall into 3 categories: developmental, genetic, and acquired. The immature lungs of premature infants are often not yet able to make sufficient amounts of surfactant, and these infants develop Respiratory Distress Syndrome (RDS) as a result of the developmental deficiency of surfactant. Surfactant protein B, SP-B, is an important component of surfactant. Infants with a genetic defect in the SP-B gene have normal lung development but poor quality surfactant. As a result, they appear to have RDS even though they were not born prematurely. Full term newborns are born with a full complement of surfactant, but diseases like pneumonia can inactivate normal surfactant, resulting in lung disease. My research focuses on the formation of alveolar type 2 cells in the developing and injured lung, especially regarding the development of surfactant components.

We have used a powerful in vitro model of alveolar type 2 cell differentiation to examine the biosynthesis of surfactant components and more recently to understand the development of lamellar bodies¿¿¿the surfactant storage organelle¿¿¿in type 2 cells. This model system has allowed us to use protease inhibitors, RNAi, and plasmids to perturb SP-B processing in vitro as type 2 cells develop. We have collaborated extensively locally, nationally, and internationally to assist other investigators in using this model to understand the transcriptional, epigenetic, and proteomic basis of development of the alveolar epithelium.

More recently, we have been investigating Hermansky-Pudlak Syndrome, a rare form of albinism associated with platelet dysfunction and lung fibrosis. Surfactant is stored in lamellar bodies, a lysosome-like subcellular organelle that is affected by mutations in HPS proteins that disrupt Biogenesis of Lysosome-related Complex trafficking, resulting in giant lamellar bodies. It remains unclear how the HPS gene products contribute to the abnormal lamellar bodies and whether this is important to lung fibrosis in HPS patients. We have a mouse model of HPS¿¿¿the double mutant pale ear/pearl mouse¿¿¿that recapitulates the development of lung disease in patients with HPS. In addition to examining the basis for abnormal lamellar body development in HPS, we are using this mouse model to understand the pathobiology of lung disease in HPS with an eye toward developing pre-clinical data for novel therapies.

In short, the focus of my research program is 1) to understand alveolar type 2 cell formation in developing lung, 2) to expand our knowledge of alveolar type 2 cell functions, and 3) to examine the contribution of alveolar type 2 cells to pulmonary physiology and pathophysiology, in both neonates and adults. Potential projects in my lab include:

¿¿¿ Regulation of gene/protein expression in differentiating alveolar type 2 cells
¿¿¿ Mechanisms of lamellar body genesis in alveolar type 2 cells
¿¿¿ Mechanisms of lung injury in Hermansky Pudlak syndrome
Research Keywords
Molecular and cell biology of alveolar epithelial cells
Jakus Z, Gleghorn JP, Enis DR, Sen A, Chia S, Liu X, Rawnsley DR, Yang Y, Hess PR, Zou Z, Yang J, Guttentag SH, Nelson CM, Kahn ML. Lymphatic function is required prenatally for lung inflation at birth. J. Exp. Med [print-electronic]. 2014 May 5/5/2014; 211(5): 815-26. PMID: 24733830, PMCID: PMC4010903, PII: jem.20132308, DOI: 10.1084/jem.20132308, ISSN: 1540-9538.

Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, Li H, Gonzales L, Baba M, Linehan WM, Gow AJ, Margulies S, Guttentag S, Schmidt LS, Krymskaya VP. Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK. Cell Rep [print-electronic]. 2014 Apr 4/24/2014; 7(2): 412-23. PMID: 24726356, PMCID: PMC4034569, PII: S2211-1247(14)00203-4, DOI: 10.1016/j.celrep.2014.03.025, ISSN: 2211-1247.

Cheong H, Wu J, Gonzales LK, Guttentag SH, Thompson CB, Lindsten T. Analysis of a lung defect in autophagy-deficient mouse strains. Autophagy [print-electronic]. 2014 Jan; 10(1): 45-56. PMID: 24275123, PMCID: PMC4028323, PII: 26505, DOI: 10.4161/auto.26505, ISSN: 1554-8635.

Beers MF, Zhao M, Tomer Y, Russo SJ, Zhang P, Gonzales LW, Guttentag SH, Mulugeta S. Disruption of N-linked glycosylation promotes proteasomal degradation of the human ATP-binding cassette transporter ABCA3. Am. J. Physiol. Lung Cell Mol. Physiol [print-electronic]. 2013 Dec; 305(12): L970-80. PMID: 24142515, PMCID: PMC3882536, PII: ajplung.00184.2013, DOI: 10.1152/ajplung.00184.2013, ISSN: 1522-1504.

Taponen S, Huusko JM, Petäjä-Repo UE, Paananen R, Guttentag SH, Hallman M, Haataja R. Allele-specific N-glycosylation delays human surfactant protein B secretion in vitro and associates with decreased protein levels in vivo. Pediatr. Res [print-electronic]. 2013 Dec; 74(6): 646-51. PMID: 24002332, PII: pr2013151, DOI: 10.1038/pr.2013.151, ISSN: 1530-0447.

Minoo P, Wolkenhauer O, Guttentag S. Systems biology and pediatric research. Pediatr. Res. 2013 Apr; 73(4 Pt 2): 499-501. PMID: 23545998, PII: pr201333, DOI: 10.1038/pr.2013.33, ISSN: 1530-0447.

Mantegazza AR, Guttentag SH, El-Benna J, Sasai M, Iwasaki A, Shen H, Laufer TM, Marks MS. Adaptor protein-3 in dendritic cells facilitates phagosomal toll-like receptor signaling and antigen presentation to CD4(+) T cells. Immunity [print-electronic]. 2012 May 5/25/2012; 36(5): 782-94. PMID: 22560444, PMCID: PMC3361531, PII: S1074-7613(12)00142-2, DOI: 10.1016/j.immuni.2012.02.018, ISSN: 1097-4180.

Mei J, Liu Y, Dai N, Hoffmann C, Hudock KM, Zhang P, Guttentag SH, Kolls JK, Oliver PM, Bushman FD, Worthen GS. Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice. J. Clin. Invest [print-electronic]. 2012 Mar; 122(3): 974-86. PMID: 22326959, PMCID: PMC3287232, PII: 60588, DOI: 10.1172/JCI60588, ISSN: 1558-8238.

Beers MF, Hawkins A, Maguire JA, Kotorashvili A, Zhao M, Newitt JL, Ding W, Russo S, Guttentag S, Gonzales L, Mulugeta S. A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling. Traffic [print-electronic]. 2011 Sep; 12(9): 1196-210. PMID: 21707890, PMCID: PMC3155663, DOI: 10.1111/j.1600-0854.2011.01223.x, ISSN: 1600-0854.

Atochina-Vasserman EN, Bates SR, Zhang P, Abramova H, Zhang Z, Gonzales L, Tao JQ, Gochuico BR, Gahl W, Guo CJ, Gow AJ, Beers MF, Guttentag S. Early alveolar epithelial dysfunction promotes lung inflammation in a mouse model of Hermansky-Pudlak syndrome. Am. J. Respir. Crit. Care Med. 2011 Aug 8/15/2011; 184(4): 449-58. PMID: 21616998, PMCID: PMC3175543, PII: 201011-1882OC, DOI: 10.1164/rccm.201011-1882OC, ISSN: 1535-4970.

Suaud L, Miller K, Alvey L, Yan W, Robay A, Kebler C, Kreindler JL, Guttentag S, Hubbard MJ, Rubenstein RC. ERp29 regulates DeltaF508 and wild-type cystic fibrosis transmembrane conductance regulator (CFTR) trafficking to the plasma membrane in cystic fibrosis (CF) and non-CF epithelial cells. J. Biol. Chem [print-electronic]. 2011 Jun 6/17/2011; 286(24): 21239-53. PMID: 21525008, PMCID: PMC3122184, PII: M111.240267, DOI: 10.1074/jbc.M111.240267, ISSN: 1083-351X.

Liu Y, Mei J, Gonzales L, Yang G, Dai N, Wang P, Zhang P, Favara M, Malcolm KC, Guttentag S, Worthen GS. IL-17A and TNF-a exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J. Immunol [print-electronic]. 2011 Mar 3/1/2011; 186(5): 3197-205. PMID: 21282514, PII: jimmunol.1002016, DOI: 10.4049/jimmunol.1002016, ISSN: 1550-6606.

Foster CD, Varghese LS, Gonzales LW, Margulies SS, Guttentag SH. The Rho pathway mediates transition to an alveolar type I cell phenotype during static stretch of alveolar type II cells. Pediatr. Res. 2010 Jun; 67(6): 585-90. PMID: 20220547, PMCID: PMC3063400, DOI: 10.1203/PDR.0b013e3181dbc708, ISSN: 1530-0447.

Johnston LC, Gonzales LW, Lightfoot RT, Guttentag SH, Ischiropoulos H. Opposing regulation of human alveolar type II cell differentiation by nitric oxide and hyperoxia. Pediatr. Res. 2010 May; 67(5): 521-5. PMID: 20098340, PMCID: PMC3066065, DOI: 10.1203/PDR.0b013e3181d4f20f, ISSN: 1530-0447.

Kotorashvili A, Russo SJ, Mulugeta S, Guttentag S, Beers MF. Anterograde transport of surfactant protein C proprotein to distal processing compartments requires PPDY-mediated association with Nedd4 ubiquitin ligases. J. Biol. Chem [print-electronic]. 2009 Jun 6/12/2009; 284(24): 16667-78. PMID: 19366705, PMCID: PMC2713532, PII: M109.002816, DOI: 10.1074/jbc.M109.002816, ISSN: 0021-9258.

Hamvas A, Heins HB, Guttentag SH, Wegner DJ, Trusgnich MA, Bennet KW, Yang P, Carlson CS, An P, Cole FS. Developmental and genetic regulation of human surfactant protein B in vivo. Neonatology [print-electronic]. 2009; 95(2): 117-24. PMID: 18776725, PMCID: PMC2765709, PII: 000153095, DOI: 10.1159/000153095, ISSN: 1661-7819.

Guttentag S. Posttranslational regulation of surfactant protein B expression. Semin. Perinatol. 2008 Oct; 32(5): 367-70. PMID: 18929160, PMCID: PMC2586979, PII: S0146-0005(08)00088-8, DOI: 10.1053/j.semperi.2008.08.003, ISSN: 1558-075X.

Gerson KD, Foster CD, Zhang P, Zhang Z, Rosenblatt MM, Guttentag SH. Pepsinogen C proteolytic processing of surfactant protein B. J. Biol. Chem [print-electronic]. 2008 Apr 4/18/2008; 283(16): 10330-8. PMID: 18256027, PMCID: PMC2447652, PII: M707516200, DOI: 10.1074/jbc.M707516200, ISSN: 0021-9258.

Foster CD, Varghese LS, Skalina RB, Gonzales LW, Guttentag SH. In vitro transdifferentiation of human fetal type II cells toward a type I-like cell. Pediatr. Res. 2007 Apr; 61(4): 404-9. PMID: 17515862, PMCID: PMC3074248, DOI: 10.1203/pdr.0b013e3180332c6d, ISSN: 0031-3998.

Wade KC, Guttentag SH, Gonzales LW, Maschhoff KL, Gonzales J, Kolla V, Singhal S, Ballard PL. Gene induction during differentiation of human pulmonary type II cells in vitro. Am. J. Respir. Cell Mol. Biol [print-electronic]. 2006 Jun; 34(6): 727-37. PMID: 16474099, PMCID: PMC2644235, PII: 2004-0389OC, DOI: 10.1165/rcmb.2004-0389OC, ISSN: 1044-1549.

Shu W, Guttentag S, Wang Z, Andl T, Ballard P, Lu MM, Piccolo S, Birchmeier W, Whitsett JA, Millar SE, Morrisey EE. Wnt/beta-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Dev. Biol. 2005 Jul 7/1/2005; 283(1): 226-39. PMID: 15907834, PII: S0012-1606(05)00249-6, DOI: 10.1016/j.ydbio.2005.04.014, ISSN: 0012-1606.

Guttentag SH, Akhtar A, Tao JQ, Atochina E, Rusiniak ME, Swank RT, Bates SR. Defective surfactant secretion in a mouse model of Hermansky-Pudlak syndrome. Am. J. Respir. Cell Mol. Biol [print-electronic]. 2005 Jul; 33(1): 14-21. PMID: 15790974, PMCID: PMC2715302, PII: 2004-0293OC, DOI: 10.1165/rcmb.2004-0293OC, ISSN: 1044-1549.

Brasch F, Birzele J, Ochs M, Guttentag SH, Schoch OD, Boehler A, Beers MF, Müller KM, Hawgood S, Johnen G. Surfactant proteins in pulmonary alveolar proteinosis in adults. Eur. Respir. J. 2004 Sep; 24(3): 426-35. PMID: 15358702, PII: 24/3/426, DOI: 10.1183/09031936.04.00076403, ISSN: 0903-1936.

Brasch F, Johnen G, Winn-Brasch A, Guttentag SH, Schmiedl A, Kapp N, Suzuki Y, Müller KM, Richter J, Hawgood S, Ochs M. Surfactant protein B in type II pneumocytes and intra-alveolar surfactant forms of human lungs. Am. J. Respir. Cell Mol. Biol [print-electronic]. 2004 Apr; 30(4): 449-58. PMID: 12972403, PII: 2003-0262OC, DOI: 10.1165/rcmb.2003-0262OC, ISSN: 1044-1549.

Foster CD, Zhang PX, Gonzales LW, Guttentag SH. In vitro surfactant protein B deficiency inhibits lamellar body formation. Am. J. Respir. Cell Mol. Biol [print-electronic]. 2003 Aug; 29(2): 259-66. PMID: 12649122, PII: 2002-0149OC, DOI: 10.1165/rcmb.2002-0149OC, ISSN: 1044-1549.

Wang G, Christensen ND, Wigdahl B, Guttentag SH, Floros J. Differences in N-linked glycosylation between human surfactant protein-B variants of the C or T allele at the single-nucleotide polymorphism at position 1580: implications for disease. Biochem. J. 2003 Jan 1/1/2003; 369(Pt 1): 179-84. PMID: 12356334, PMCID: PMC1223069, PII: BJ20021376, DOI: 10.1042/BJ20021376, ISSN: 0264-6021.

Gonzales LW, Guttentag SH, Wade KC, Postle AD, Ballard PL. Differentiation of human pulmonary type II cells in vitro by glucocorticoid plus cAMP. Am. J. Physiol. Lung Cell Mol. Physiol. 2002 Nov; 283(5): L940-51. PMID: 12376347, DOI: 10.1152/ajplung.00127.2002, ISSN: 1040-0605.

Sotiriou S, Gispert S, Cheng J, Wang Y, Chen A, Hoogstraten-Miller S, Miller GF, Kwon O, Levine M, Guttentag SH, Nussbaum RL. Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. Nat. Med. 2002 May; 8(5): 514-7. PMID: 11984597, PII: nm0502-514, DOI: 10.1038/nm0502-514, ISSN: 1078-8956.