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Michael J. Holtzman, M.D.
Michael J. Holtzman, M.D.

Michael J. Holtzman, M.D.

Seldin Professor and Director
Pulmonary & Critical Care Medicine

Washington University School of Medicine
660 S. Euclid Avenue, Campus Box 8052
St. Louis, MO 63110
(314) 362-8983 (phone)
(314) 362-8987 (fax)

mholtzma@im.wustl.edu

Research Interests

Acute and chronic responses to respiratory viruses.

Biographical Sketch

Research

My lab focuses on the basis for mucosal immunity, inflammation, and remodeling, especially in relation to lung disease. We concentrate on the response to respiratory paramyxoviruses, since these agents are most commonly associated with acute and chronic obstructive lung diseases. We use viral, cellular, and mouse models as well as human subjects for study, and we take advantage of genomics, genetics, immunology, virology, and cell, molecular, and structural biology. Our approach aims to determine which factors control acute paramyxoviral infection and how transient infections cause chronic inflammatory airway disease.

We have shown that viral immunity depends on a special network of immune-response genes in airway epithelial cells, macrophages, and dendritic cells, and these signals are being refined as targets for new antiviral strategies. We have also discovered that viruses can permanently activate an alternative immune axis that depends on dendritic cells, NKT cells, NBNT cells, and macrophages to drive chronic airway disease. These new immune pathways are also being defined in patients with airway disease due to asthma and COPD.

Publications

1.Holtzman, M. J., Cunningham, J. H., Sheller, J. R., Irsigler, G. B., Nadel, J. A., and Boushey, H. A. Effect of ozone on bronchial reactivity in atopic and non-atopic subjects. (1979) Am. Rev. Respir. Dis. 120, 1059-1067.

2.Holtzman, M. J., Sheller, J. R., DiMeo, M., Nadel, J. A., and Boushey, H. A. Effect of ganglionic blockade on bronchial reactivity in atopic subjects. (1980) Am. Rev. Respir. Dis. 122, 17-25.

3.Boushey, H. A., Holtzman, M. J., Sheller, J. R., and Nadel, J. A. State of the art: Bronchial hyperreactivity. (1980) Am. Rev. Respir. Dis. 121, 389-413.

4.DiMeo M. J., Glenn, M. G., Holtzman, M. J., Sheller, J. R., Nadel, J. A., and Boushey, H. A. Threshold concentration of ozone causing an increase in bronchial reactivity in humans and adaptation with repeated exposures. (1981) Am. Rev. Respir. Dis. 124, 245-248.

5.Holtzman, M. J., and Nadel, J. A. Treatment of asthma and bronchoconstriction. (1981) Ration. Drug. Ther. 15, 1-6.

6.Sheller, J. R., Holtzman, M. J., Skoogh, B.-E., and Nadel, J. A. Interaction of serotonin with vagal- and ACh-induced bronchoconstriction in canine lungs. (1982) J. Appl. Physiol. 52, 964-966.

7.Holtzman, M. J., Hahn, H. L., Sasaki, K. A., Skoogh, B.-E., Graf, P. D., and Nadel, J. A. Selective effect of general anesthetics on reflex bronchoconstrictor responses in dogs. (1982) J. Appl. Physiol. 53, 126-133.

8.Sheppard D., Epstein, J., Holtzman, M. J., Nadel, J. A., and Boushey, H. A. Dose-dependent inhibition of cold air-induced bronchoconstriction by atropine. (1982) J. Appl. Physiol. 53, 169-174.

9.Skoogh, B.-E., Holtzman, M. J., Sheller, J. R., and Nadel, J. A. Barbiturates depress the vagal motor pathway to ferret trachea at ganglia. (1982) J. Appl. Physiol. 53, 253-257.

10.Holtzman, M. J., McNamara, M. P., Sheppard, D., Fabbri, L. M., Hahn, H. L., Graf, P. D., and Nadel, J. A. Intravenous versus inhaled atropine for inhibiting bronchoconstrictor responses in dogs. (1983) J. Appl. Physiol. 54, 134-139.

11.Sheppard, D., Epstein, J., Holtzman, M. J., Nadel, J. A., and Boushey, H. A. Effect of route of atropine delivery on bronchospasm from cold air and methacholine. (1983) J. Appl. Physiol. 54, 130-133.

12.Skoogh, B.-E., Nadel, J. A., Fabbri, L. M., Sheppard, D., and Holtzman, M. J. Antihistaminic versus anticholinergic effects of atropine in canine trachealis muscle. (1983) Am. Rev. Respir. Dis. 128, 603-606.

13.Holtzman, M. J., Fabbri, L. M., Skoogh, B.-E., O'Byrne, P. M., Walters, E. H., Aizawa, H., and Nadel, J. A. Time course of airway hyperresponsiveness induced by ozone in dogs. (1983) J. Appl. Physiol. 55, 1232-1236.

14.Holtzman, M. J., Fabbri, L. M., O'Byrne, P. M., Gold, B. D., Aizawa, H., Walters, E. H., Alpert, S. E., and Nadel, J. A. Importance of airway inflammation for hyperresponsiveness induced by ozone. (1983) Am. Rev. Respir. Dis. 127, 686-690.

15.Holtzman, M. J., Aizawa, H., Nadel, J. A., and Goetzl, E. J. Selective generation of leukotriene B4 by tracheal epithelial cells from dogs. (1983) Biochem. Biophys. Res. Commun. 114, 1071-1076.

16.Fabbri, L. M., Aizawa, H., Alpert, S. E., Walters, E. H., O'Byrne, P. M., Gold, B. D., Nadel, J. A., and Holtzman, M. J. Airway hyperresponsiveness and changes in cell counts in bronchoalveolar lavage after ozone exposure in dogs. (1984) Am. Rev. Respir. Dis. 129, 288-291.

17.O'Byrne, P. M., Walters, E. H., Gold, B. D., Aizawa, H., Fabbri, L. M., Nadel, J. A., and Holtzman, M. J. Neutrophil depletion inhibits airway hyperresponsiveness induced by ozone exposure. (1984) Am. Rev. Respir. Dis. 130, 214-219.

18.O'Byrne, P. M., Walters, E. H., Aizawa, H., Fabbri, L. M., Holtzman, M. J., and Nadel, J. A. Indomethacin inhibits the airway hyperresponsiveness but not the neutrophil influx induced by ozone in dogs. (1984) Am. Rev. Respir. Dis. 130, 220-224.

19.O'Byrne, P. M., Aizawa, H., Bethel, R. A., Chung, K. F., Nadel, J. A., and Holtzman, M. J. Prostaglandin F2? increases responsiveness of pulmonary airways in dogs. (1984) Prostaglandins 28, 537-543.

20.Walters, E. H., O'Byrne, P. M., Fabbri, L. M., Graf, P. D., Holtzman, M. J., and Nadel, J. A. Control of neurotransmission by prostaglandins in canine trachealis muscle. (1984) J. Appl. Physiol. 57, 129-134.

21.Fabbri, L. M., Aizawa, H., O'Byrne, P. M., Bethel, R. A., Holtzman, M. J., and Nadel, J. A. An anti-inflammatory drug (BW755c) inhibits airway hyperresponsiveness induced by ozone in dogs. (1985) J. Allergy Clin. Immunol. 76, 162-166.

22.O'Byrne, P. M., Leikauf, G. D., Aizawa, H., Bethel, R. A., Ueki, I. F., Holtzman, M. J., and Nadel, J. A. Leukotriene B4 causes airway hyperresponsiveness in dogs. (1985) J. Appl. Physiol. 59, 1941-1946.

23.Hunter, J. A., Finkbeiner, W. E., Nadel, J. A., Goetzl, E. J., and Holtzman, M. J. Predominant generation of 15-lipoxygenase metabolites of arachidonic acid by epithelial cells from human trachea. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 4633-4637.

24.Boushey, H. A., and Holtzman, M. J. Experimental airway inflammation and hyper-responsiveness: searching for cells and mediators. (1985) Am. Rev. Respir. Dis. 131, 312-313.

25.Seltzer, J., Bigby, B. G., Stulbarg, M.J., Holtzman, M. J., Nadel, J. A., Ueki, I. F., Leikauf, G. D., Goetzl, E. J., and Boushey, H. A. Ozone-induced change in bronchial reactivity to methacholine and airway inflammation in humans. (1986) J. Appl. Physiol. 60, 1321-1326.

26.Holtzman, M. J., Grunberger, D., and Hunter, J. A. Phospholipid fatty acid composition of pulmonary airway epithelial cells: potential substrates for oxygenation. (1986) Biochim. Biophys. Acta. 877, 459-464.

27.Holtzman, M. J. Cellular basis of bronchial hyperresponsiveness: lipoxygenation of arachidonic acid in tracheal epithelial cells. (1986) Bull. Eur. Physiopathol. Respir. 22 (Suppl 7), 38.

28.Sigal, C. E., Valone, F. H., Holtzman, M. J., and Goetzl, E. J. Preferential human eosinophil chemotactic activity of the platelet-activating factor (PAF) 1-O-hexadecyl-2-acetyl-sn-glyceryl-3-phosphocholine (AGEPC). (1987) J. Clin. Immunol. 7, 179-184.

29.Bigby, T. D., and Holtzman, M. J. Enhanced 5-lipoxygenase activity in pulmonary macrophages compared to monocytes from normal subjects. (1987) J. Immunol. 138, 1546-1550.

30.Holtzman, M. J., Hansbrough, J. R., Rosen, G. D., and Turk, J. Uptake, release, and novel species-dependent oxygenation of arachidonic acid in human and animal airway epithelial cells. (1988) Biochim. Biophys. Acta 963, 401-413.

31.Holtzman, M. J., Pentland, A., Baenziger, N. L, and Hansbrough, J. R. Heterogeneity of cellular expression of arachidonate 15-lipoxygenase: implications for biological activity. (1989) Biochim. Biophys. Acta. 1003, 204-208.

32.Hansbrough, J. R., Atlas, A. B, Turk, J., and Holtzman, M. J. Arachidonate 12-lipoxygenase and cyclooxygenase:PGE isomerase are predominant pathways for oxygenation in bovine tracheal epithelial cells. (1989) Am. J. Respir. Cell Mol. Biol. 1:237-244.

33.Holtzman, M. J., Turk, J., and Pentland, A. A regiospecific monooxygenase with novel stereopreference is the major pathway for arachidonic acid oxygenation in isolated epidermal cells. (1989) J. Clin. Invest. 84:1446-1453.

34.Rosen, G. D., Birkenmeier, T. M., Raz, A., and Holtzman, M. J. Identification of a cyclooxygenase-related gene and its potential role in prostaglandin formation. (1989) Biochem. Biophys. Res. Commun. 164:1358-1365.

35.Hansbrough, J. R., Takahashi, Y., Ueda, N., Yamamoto, S., and Holtzman, M. J. Identification of a novel arachidonate 12-lipoxygenase in bovine tracheal epithelial cells distinct from leukocyte and platelet forms of the enzyme. (1990) J. Biol. Chem. 265:1771-1776.

36.Holtzman, M. J. Mechanisms of lipid mediator release in airway epithelial cells. (1990) Immunol. Allergy Clin. N. Am. 10:309-318.

37.Pentland, A. P., Mahoney, M., Jacobs, S. C., and Holtzman, M. J. Enhanced prostaglandin synthesis after ultraviolet injury is mediated by endogenous histamine stimulation: a mechanism for irradiation erythema. (1990) J. Clin. Invest. 86:566-574.

38.Holtzman, M. J., Ferdman, B., Bohrer, A., and Turk, J. Synthesis of the 1-O-hexadecyl molecular species of platelet-activating factor by airway epithelial cells and vascular endothelial cells. (1991) Biochem. Biophys. Res. Commun. 177:357-364.

39.Shannon, V. R., Crouch, E. C., Ueda, N., Takahashi, Y., Yamamoto, S., and Holtzman, M. J. Related expression of arachidonate 12- and 15-lipoxygenases in animal and human lung tissue. (1991) Am. J. Physiol. (Lung Cell. Mol. Physiol.) 261:L399-L405.

40.Holtzman, M. J. State of the art. Arachidonic acid metabolism: implications of biological chemistry for lung function and disease. (1991) Am. Rev. Respir. Dis. 143:188-203.

41.Look, D. C., Rapp, S. R., Keller, B. T., and Holtzman, M. J. Selective induction of intercellular adhesion molecule-1 by interferon-? in human airway epithelial cells. (1992) Am. J. Physiol. (Lung Cell. Mol. Physiol.) 263:L79-87.

42.Shannon, V. R., Ramanadhan, S., Turk, J., and Holtzman, M. J. Selective expression of an arachidonate 12-lipoxygenase by pancreatic islet ?-cells. (1992) Am. J. Physiol. (Endocrinol. Metab.) 263:E828-E836.

43.Holtzman, M. J., Turk, J., and Shornick, L. P. Identification of a pharmacologically-distinct prostaglandin H synthase in cultured epithelial cells. (1992) J. Biol. Chem. 267:21438-21445.

44.Holtzman, M. J. Arachidonic acid metabolism in airway epithelial cells. (1992) Annu. Rev. Physiol. Vol. 54, pp. 303-329.

45.Holtzman, M. J., and Look, D. C. Cell adhesion molecules as targets for unraveling the genetic regulation of airway inflammation. (1992) Am. J. Respir. Cell Mol. Biol. 7:246-247.

46.Shannon, V. R., Stenson, W. F., and Holtzman, M. J. Induction of epithelial arachidonate 12-lipoxygenase at active sites of inflammatory bowel disease. (1993) Am. J. Physiol. (Gastrointest. Liver Physiol.) 264:G104-G111.

47.Shornick, L. P., and Holtzman, M. J. A cryptic, microsomal-type arachidonate 12-lipoxygenase is tonically inactivated by oxidation-reduction conditions in cultured epithelial cells. (1993) J. Biol. Chem. 268:371-376.

48.Shannon, V. R., Chanez, P., Bousquet, J., and Holtzman, M. J. Histochemical evidence for induction of arachidonate 15-lipoxygenase in airway disease. (1993) Am. Rev. Respir. Dis. 147:1024-1028.

49.Hussain, H., Shornick, L. P., Shannon, V. R., Wilson, J. D., Funk, C. D., Pentland, A. P., and Holtzman, M. J. Epidermis contains a platelet-type 12-lipoxygenase that is selectively overexpressed in germinal layer keratinocytes in psoriasis. (1994) Am. J. Physiol. (Cell Physiol.) 266:C243-C253.

50.Look, D. C., Pelletier, M. R., and Holtzman, M. J. Selective interaction of a subset of interferon-?-response element binding proteins with the intercellular adhesion molecule-1 (ICAM-1) gene promoter controls the pattern of expression on epithelial cells. (1994) J. Biol. Chem. 269:8952-8958.

51.Nakajima, S., Look, D. C., Roswit, W. T., Bragdon, M. J., and Holtzman, M. J. Selective differences in vascular endothelial- vs. airway epithelial-T cell adhesion mechanisms. (1994) Am. J. Physiol. (Lung Cell. Mol. Physiol.) 267:L422-L432.

52.Dean, D. C., Weintraub, S. J., and Holtzman, M. J. A molecular switch between lung development and cancer: is the tumor suppressor Rb turned on in bronchial epithelial cell differentiation and turned off in small cell lung cancer? (1994) Am. J. Respir. Cell Mol. Biol. 11:249-250.

53.Nakajima, S., Roswit, W. T., Look, D. C., and Holtzman, M. J. A hierarchy for integrin expression and adhesiveness among T cell subsets that is linked to TCR gene usage and emphasizes V?1+ ?? T cell adherence and tissue retention. (1995) J. Immunol. 155:1117-1131.

54.Look, D. C., Pelletier, M. R., Tidwell, R. M., Roswit, W. T., and Holtzman, M. J. Accelerated communication: Stat1 depends on transcriptional synergy with Sp1. (1995) J. Biol. Chem. 270:30264-30267.

55.Holtzman, M. J., Brody, S. L., and Look, D. C. Does gene therapy call for "STAT" immunity and inflammation at the epithelial barrier? (1995) Am. J. Respir. Cell Mol. Biol. 12:127-129.

56.Zhang, V., O'Sullivan, M., Hussain, H., Roswit, W. T., and Holtzman, M. J. Molecular cloning, functional expression, and selective regulation of ovine prostaglandin H synthase-2. (1996) Biochem. Biophys. Res. Commun. 227:499-506.

57.Holtzman, M. J., Sampath, D., Castro, M, Look, D. C., and Jayaraman, S. The one-two of T helper cells: does interferon-? knockout the Th2 hypothesis for asthma? (1996) Am. J. Respir. Cell Mol. Biol. 14:316-318.

58.Walter, M. J., Look, D. C., Tidwell, R. M., Roswit, W. T., and Holtzman, M. J. Targeted inhibition of interferon-?-dependent intercellular adhesion molecule-1 (ICAM-1) expression using dominant-negative Stat1. (1997) J. Biol. Chem. 272:28582-28589.

59.Holtzman, M. J., Look, D. C., Sampath, D., Castro, M., Koga, T., and Walter, M. J. Control of epithelial immune-response genes and implications for airway immunity and inflammation. (1998) Proc. Assoc. Am. Phys. 110:1-11.

60.Taguchi, M., Sampath, D., Koga, T., Castro, M., Look, D. C., Nakajima, S., and Holtzman, M. J. Patterns for RANTES secretion and intercellular adhesion molecule-1 expression mediate transepithelial T cell traffic based on analyses in vitro and in vivo. (1998) J. Exp. Med. 187:1927-1940.

61.Holtzman, M. J. Matching scientific with societal interests: charges for the new editor. (1998) Am. J. Respir. Cell Mol. Biol. 19:1-2.

62.Look, D. C., Roswit, W. T., Frick, A. G., Dickhaus, D. M., Gris-Alevy, Y., Walter, M. J., and Holtzman, M. J. Direct suppression of Stat1 function during adenoviral infection. (1998) Immunity 9:871-880.

63.Jayaraman, S., Castro, M., O'Sullivan, M., Bragdon, M. J., and Holtzman, M. J. Resistance to Fas-mediated T cell apoptosis in asthma. (1999) J. Immunol. 162:1717-22.

64.Koga, T., Sardia, E., Tidwell, R. M., Pelletier, M. R., Look, D. C., and Holtzman, M. J. Virus-inducible expression of a host chemokine gene relies on replication-linked mRNA stabilization. (1999) Proc. Natl. Acad. Sci. U. S. A. 96:5680-5685.

65.Sampath, D., Castro, M., Look, D. C., Holtzman, M. J. Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. (1999) J. Clin. Invest. 103:1353-1361.

66.Holtzman, M. J. Erasing the surplus (in publication and review times) by deficit spending. (1999) Am. J. Respir. Cell Mol. Biol. 21:6.

67.Castro, M., Walter, M. J., Chaplin, D. D., and Holtzman, M. J. Could asthma worsen by stimulating the T helper type 1 (Th1) response? (2000) Am. J. Respir. Cell Mol. Biol. 22:143-146.

68.Shen, X., Tian, Z., Holtzman, M. J., and Gao, B. Cross-talk between interleukin-1? (IL-1?) and IL-6 signaling pathways: IL-1? selectively inhibits IL-6-activated signal transducer and activator of transcription factor 1 (Stat1) by a proteasome-dependent mechanism. (2000) Biochem. J. 352:913-919.

69.Holtzman, M. J. Perennial goals for the millennium. (2000) Am. J. Respir. Cell Mol. Biol. 23:1-2.

70.Holtzman, M. J., Green, J. M., Jayaraman, S., and Arch, R. H. Regulation of T cell apoptosis. (2000) Apoptosis 5:457-469.

71.Walter, M. J., Kajiwara, N., Karanja, P., Castro, M., and Holtzman, M. J. IL-12 p40 production by barrier epithelial cells during airway inflammation. (2001) J. Exp. Med. 193:339-352.

72.Holtzman, M. J. Electronics, people, and the art of publication. (2001) Am. J. Respir. Cell Mol. Biol. 25:1-2.

73.Anderson, G. J., Roswit, W. T., Holtzman, M. J., Hogg, J. C., and van Eeden, S. F. The effect of mechanical deformation of neutrophils on their CD18/ICAM-1-dependent adhesion. (2001) J. Appl. Physiol. 91:1084-1090.

74.Iregui, M., Malen, J., Tuteur, P., Lynch, J., Holtzman, M. J., Kollef, M. H. Determinants of outcome for patients admitted to a long-term ventilator unit. (2002) Southern Med. J. 95:310-317.

75.Chang, Y.-J., Holtzman, M. J., and Chen, C.-C. Interferon-?-induced epithelial ICAM-1 expression and monocyte adhesion. Involvement of protein kinase C-dependent c-Src tyrosine kinase activation pathway. (2002) J. Biol. Chem. 277:7118-7119.

76.Holtzman, M. J., Morton, J. D., Shornick, L. P., Tyner, J. W., OSullivan, M. P., Antao, A., Lo, M., Castro, M., and Walter, M. J. Immunity, inflammation, and remodeling in the airway epithelial barrier: epithelial-viral-allergic paradigm. (2002) Physiol. Rev. 82:19-46.

77.Walter, M. J., Morton, J.D., Kajiwara, N., Agapov, E., and Holtzman, M. J. Viral induction of a chronic asthma phenotype and genetic segregation from the acute response. (2002) J. Clin. Invest. 110:165-175.

78.Holtzman, M. J. Improving peer review and introducing translational review. (2002) Am. J. Respir. Cell Mol. Biol. 27:1-2.

79.Stephens, R., Randolph, D. A., Huang, G., Holtzman, M. J., and Chaplin, D. D. Antigen-nonspecific recruitment of Th2 cells to the lung as a mechanism for viral infection-induced allergic asthma. (2002) J. Immunol. 169:5458-5467.

80.Grayson, M. H., and Holtzman, M. J. Lessons from allergic rhinitis versus asthma pathogenesis and treatment. (2002) Immunol. Allergy Clin. N. Am. 22:845-869.

81.Holtzman, M. J. Where are the gaps in asthma research? A counter-perspective. (2003) J. Allergy Clin. Immunol.111:244-247.

82.Huang, X., Pawliczak, R., Yao, X., Cowan, M. J., Gladwin, M. T., Walter, M. J., Holtzman, M. J., and Shelhamer, J. H. Interferon-? induces p11 gene and protein expression in human epithelial cells through interferon-?-activated sequences in the p11 promoter. (2003) J. Biol. Chem. 278:9298-9308.

83.Grayson, M. H., Hotchkiss, R. S., Karl, I. E., Holtzman, M. J., and Chaplin, D. D. Intravital microscopy comparing T lymphocyte trafficking to the spleen and the mesenteric lymph node. (2003) Am. J. Physiol. (Heart Circ. Physiol.) 284:H2213-2226.

84. Holtzman, M. J. Transition, sunshine, and the art of journal maintenance. (2003) Am. J. Respir. Cell Mol. Biol. 29:1-2.

85.Holtzman, M. J., Agapov, E., Kim, E., Kim, J., and Morton, J. D. Developing the epithelial, viral, and allergic paradigm for asthma (2003) Chest 123:377S-384S.

86. OSullivan, M., Tyner, J. W., Holtzman, M. J. Apoptosis in the airways: another balancing act in the epithelial program. (2003) Am. J. Respir. Cell Mol.. Biol. 29:3-7.

87.Castro, M., Block, S. R., Jenkersen, M. V., DeMartino, S., Hamilos, D. L., Cochran, R. B., E, X., Zhang, L., Wang, H., Bradley, J. P., Schechtman, K. B., and Holtzman, M. J. Asthma exacerbation after glucocorticoid withdrawal reflects T cell recruitment to the airway. (2004) Am. J. Respir. Crit. Care Med. 169:842-849.

88.Chang, Y.-J., Holtzman, M. J., and Chen, C.-C. Differential role of Janus family kinases (JAKs) in interferon-?-induced lung epithelial ICAM-1 expression: involving protein interactions between JAKs, phospholipase C?, c-Src, and Stat1. (2004) Mol. Pharmacol. 65:589-598.

89.Holtzman, M. J. Drug development for asthma. (2004) Am. J. Respir. Cell Mol. Biol. 29:163-179.

90.Holtzman, M. J., Shornick, L. P., Grayson, M. H., Kim, E. Y., Tyner, J. W., Patel, A. C., Agapov, E., and Zhang. Y. Hit-and-run effects of paramyxoviruses as a basis for chronic respiratory disease. (2004) Pediatr. Infect. Dis. J. 23:S235-S245.

91.Holtzman, M. J., Kim, E. Y., Lo, M. S., Tyner, J. W., Shornick, L. P., Sumino, K. C., and Zhang, Y. Defining and adjusting divergent host responses to viral infection. (2005) Immunol. Res. 32:123-142.

92.Walter, M. J., and Holtzman, M. J. A centennial history of research on asthma pathogenesis. (2005) Am. J. Respir. Cell Mol. Biol. 32:483-489.

93.Sumino, K. C., Agapov, E., Pierce, R. A., Trulock, E. P., Pfeifer, J. D., Ritter, J. H., Gaudreault-Keener, M., Storch, G. A., and Holtzman, M. J. Detection of severe human metapneumovirus infection by real-time polymerase chain reaction and histopathological assessment. (2005) J. Infect. Dis. 192:1052-1060.

94.Holtzman, M. J. Chairmans Summary. Twentieth Transatlantic Airway Conference: Airway responses to respiratory viruses. (2005) Proc. Am. Thorac. Soc. 2:108-109.

95.Holtzman, M. J., Tyner, J. W., Kim, E. Y., Lo, M. S., Patel, A. C., Shornick, L. P., Agapov, E., and Zhang, Y. Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease. (2005) Proc. Am. Thorac. Soc. 2:132-140.

96.Lo, M. S., Brazas, R. M., and Holtzman, M. J. Respiratory syncytial virus nonstructural proteins NS1 and NS2 mediate inhibition of Stat2 expression and type I interferon responsiveness. (2005) J. Virol. 79:9315-9319. (Selected as Spotlight Article, see J. Virol. 79:8675-8676, 2005)

97.Tyner, J. W., Uchida, O., Kajiwara, N., Kim, E. Y., Patel, A.C., OSullivan, M.P., Walter, M. J., Schwendener, R. A, Cook, D. N., Danoff, T. M., and Holtzman, M. J. CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. (2005) Nat. Med. 11:1180-1187.

98.Zhang, Y., Takami, K., Lo, M. S., Huang, G., Yu, Q., Roswit, W. T., and Holtzman, M. J. Modification of the STAT1 SH2 domain broadly improves interferon efficacy in proportion to p300/CBP coactivator recruitment. (2005) J. Biol. Chem. 280:34306-34315. (Selected as Paper of the Week, see J. Biol. Chem. 280:e99946, 2005)

99.Agapov, E., Sumino, K. C., Gaudreault-Keener, M., Storch, G. A., and Holtzman, M. J. Genetic variability of human metapneumovirus infection: evidence of a shift in viral genotype without a change in illness. (2006) J. Infect. Dis. 193:396-403.

100.Tyner, J. W., Kim, E. Y., Ide, K., Pelletier, M. R., Roswit, W. T., Morton, J. D., Battaile, J. T., Patel, A. C., Patterson, G. A., Castro, M., Spoor, M. S., You, Y., Brody, S. L., and Holtzman, M. J. Blocking airway mucous cell metaplasia by inhibiting EGFR anti-apoptosis and IL-13 transdifferentiation signals. (2006) J. Clin. Invest.116:309-321.

101.Grayson, M. H. and Holtzman, M. J. Chemokine signaling regulates apoptosis as well as immune cell traffic in host defense. (2006) Cell Cycle 5:380-383.

102.Deppong, C., Juehne, T. I., Hurchla, M., Friend, L. D., Shah, D. D., Rose, C. M., Bricker, T. L., Shornick, L. Crouch, E., Murphy, T. L., Holtzman, M. J., Murphy, K. M., and Green, J. M. Cutting edge: B and T lymphocyte attenuator and programmed death receptor-1 inhibitory receptors are required for termination of acute allergic airway inflammation. (2006) J. Immunol. 176:3909-3913.

103.Adler, K. B., Shapiro, S. D., Gallup, M., Wu, R., Randell, S. H., Holtzman, M. J., Evans, C. M., Jacoby, D. B., Tesfaigzi, Y., Rose, M. C., Mossman, B. T., Prince, A., Reddy, S. P., Davis, C. W., and Matthay, M. A. Airway epithelium, inflammation, and mechanisms of disease: a tribute to Carol B. Basbaum. Preface to series. (2006) Am. J. Respir. Cell Mol. Biol. 34:523-526.

104.Holtzman, M. J., Battaile, J. T., and Patel, A. C. Immunogenetic programs for viral induction of mucous cell metaplasia. (2006) Am. J. Respir. Cell Mol. Biol. 35:29-39.

105.Patel, A. C., Morton, J. D., Kim, E. Y., Alevy, Y., Swanson, S., Tucker, J., Huang, G., Agapov, E., Phillips, T. E., Fuentes, M. E., Iglesias, A., Aud, D., Allard, J. D., Dabbagh, K., Peltz, G., and Holtzman, M. J. Genetic segregation of airway disease traits despite redundancy of calcium-activated chloride channel family members. (2006) Physiol. Genomics 25:502-513.

106.Ibricevic, A., Pekosz, A. S., Walter, M. J., Newby, C., Battaile, J. T., Brown, E. G., Holtzman, M. J., and Brody, S. L. Influenza virus receptor specificity and cell tropism in mouse and human airway epithelial cells. (2006) J. Virol. 80:7469-7480.

107.Lin, W., Kim, S. S., Yeung, E., Kamegaya, Y., Blackard, J. T., Kim, K. A., Holtzman, M. J., and Chung, R. T. Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. (2006) J. Virol.80:9226-92235.

108.Grayson, M. H. and Holtzman, M. J. Chemokine complexity: the case for CCL5. (2006) Am. J. Respir. Cell Mol. Biol. 35:143-146.

109.Zhang, Y., Huang, G., Shornick, L. P., Roswit, W. T., Shipley, J. M., Brody, S. L., and Holtzman, M. J. A transgenic FOXJ1-Cre system for gene inactivation in ciliated epithelial cells. (Rapid Communication) (2007) Am. J. Respir. Cell Mol. Biol. 36:515-519.

110.Kwon, M., Walter, M. J., Holtzman, M. J., and Chang, C.-H. PKCdelta regulates IFN-gamma-inducible expression of CIITA via Stat1 serine phosphorylation. (2007) Mol. Immunol. 44:2841-2849.

111.Grayson, M. H. and Holtzman, M. J. Emerging roles of dendritic cells in respiratory viral infection. (2007) J. Mol. Med in press.

112.Cohen, L. E, X., Tarsi, J., Ramkumar, T., Horiuchi, T. K., Cochran, R., DeMartino, S., Schechtman, K. B., Hussain, I., Holtzman, M. J., and Castro, M. Epithelial cell proliferation contributes to airway remodeling in severe asthma. (2007) Am. J. Respir. Crit. Care Med. 176:138-145.

113.Grayson, M. H., Ramos, M. S., Rohlfing, M. M., Kitchens, R., Wang, H. D., Gould, A., Agapov, E., and Holtzman, M. J. Controls for lung dendritic cell maturation and migration during respiratory viral infection. (2007) J. Immunol. 179:1438-1448.

114.Stout, B. A., Rir-Sim-ah, J., Seagrave, J., Holtzman, M. J., Xiang, J., and Tesfaigzi, Y. Activation of Stat1 by IFN-? causes cell death in epithelial cells by translocating Bax to the endoplasmic reticulum. (2007) J. Immunol. 178:8107-8116.

115.Grayson, M. H., Cheung, D., Rohlfing, M. M., Kitchens, R., Spiegel, D. E., Tucker, J., Battaile, J., Alevy, Y., Yan, L., Agapov, E., Kim, E. Y., and Holtzman, M. J. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. (2007) J. Exp. Med. In press.

116.Shornick, L. P., Wells, A., Zhang, Y., Patel, A. C., Huang, G., Takami, K., Sosa, M., Shukla, N. A., Agapov, E., and Holtzman, M. J. Airway epithelial versus immune cell Stat1 function for innate defense against respiratory viral infection. (2007) J. Immunol.in revision.

117.Kim, E. Y., Battaile, J. T., Patel, A. C., Agapov, E., Grayson, M. H., You, Y., Alevy, Y., Tucker, J., Swanson, S., Tyner, J. W., Morton, J. D., Castro, M., Patterson, G. A., Schwendener, R. A., Allard, J. D., Peltz, G., and Holtzman, M. J. (2007) Persistent activation of a novel innate immune response drives the transition from acute viral infection to chronic inflammatory lung disease. in revision.

118Fujisawa, T., Ide, K., Holtzman, M. J., Suda, T., Suzuki, K., Kuroishi, S., Chida, K., Nakamura, H. Involvement of the p38MAPK pathway in IL-13-induced mucous metaplasia in mouse tracheal epithelial cells. (2007) Respirol. in press.

119.Akk, A., Simmons, P. M., Chan, H., Agapov, E., Holtzman, M. J., Grayson, M. H., and Pham, C. T. N. The absence of DPPI attenuates the acute inflammatory response to Sendai virus infection. (2007) J. Immunol. in revision.

120.Zhang, Y., Takami, K. MD; Huang, G., Yu, Q., Lo, M. S., Roswit, W. T., and Holtzman, M. J. Protection against viral infection using a transgene that confers interferon hyperresponsivenes (2007) submitted.

Book Chapters/Reviews

1.Boushey, H. A., and Holtzman, M. J. Bronchodilators and other agents used in the treatment of asthma. (1982) in Basic and Clinical Pharmacology (Katzung, B. G., editor), (1982) pp. 205-213, (Lange, Los Altos, California).

2.Holtzman, M. J. Pathophysiology of asthma: an overview of mechanisms of bronchial hyperreactivity. (1982) in Bronchial Hyperreactivity (Morley, J., editor), pp. 5-19, (Academic Press, London).

3.Nadel, J. A., and Holtzman, M. J. Regulation of airway responsiveness and secretion: role of inflammation. (1984) in Asthma: Physiology, Immunopharmacology, and Treatment (Kay, B. A., Austen, K. F., Lichtenstein, L. M., editors), pp. 129-153, (Academic Press, London).

4.Boushey, H. A., and Holtzman, M. J. Bronchodilators and other agents used in the treatment of asthma. (1984) in Basic and Clinical Pharmacology (Katzung, B. G., editor), 2nd edition, pp. 227-238, (Lange, Los Altos, California).

5.Boushey, H. A., and Holtzman, M. J. Autonomic regulation of airways: parasympathetic nervous system. (1985) in Bronchial Asthma: Mechanisms and Therapeutics (Weiss, E. B., Segal, M. S., Stein, M., editors), pp. 111-122, (Little, Brown and Co., Boston).

6.Holtzman, M. J. Inflammation of the airway epithelium and the development of airway hyperresponsiveness. (1985) in Prog. Respir. Res., Asthma and Bronchial Hyperreactivity (Herzog, H., Perruchoud, A. P., editors), Vol. 19, pp. 165-172, (Karger, Basel).

7.Nadel, J. A., Barnes, P. J., and Holtzman, M. J. Autonomic factors in hyperreactivity of airway smooth muscle. (1986) in Handbook of Physiology: The Respiratory System (Macklem, P. T., Mead, J., editors), pp. 693-702, (American Physiological Society, Bethesda, Maryland).

8.Holtzman, M. J. Species-specificity of lipoxygenase and cyclooxygenase activities expressed in pulmonary airway epithelial cells. (1987) Adv. Prostaglandin Thromboxane Leukotriene Res. 17A:177-179 (Raven Press, New York).

9.Boushey, H. A., and Holtzman, M. J. Bronchodilators and other agents used in the treatment of asthma. (1987) in Basic and Clinical Pharmacology (Katzung, B. G., editor), 3rd edition, pp. 222-232, (Prentice-Hall, Englewood Cliffs, New Jersey).

10.Shannon, V. R., Hansbrough, J. R., Takahashi, Y., Ueda, N., Yamamoto, S., and Holtzman, M. J. Biochemical and immunohistochemical evidence for selective expression of novel epithelial lipoxygenases. (1990) Adv. Prostaglandin Thromboxane Leukotriene Res. 21A:37-40 (Raven Press, New York).

11.Holtzman, M. J. Sources of inflammatory mediators in the lung: the role of epithelial and leukocyte pathways for arachidonic acid oxygenation. (1991) in Mediators of Pulmonary Inflammation, Lung Biology in Health and Disease (Bray, M. A., Anderson, W. H., editors), Vol. 54, pp. 279-325 (Marcel Dekker, New York).

12.Holtzman, M. J. Epithelial cell regulation of arachidonic acid oxygenation. (1991) in The Airway Epithelium: Physiology, Pathophysiology, and Pharmacology, Lung Biology in Health and Disease (Farmer, S. G., Hay, D. W. P., editors), Vol. 55, pp. 65-115 (Marcel Dekker, New York).

13.Holtzman, M. J., Shannon, V. R., Masi, A. M., and Look, D. C. Mechanisms of airway inflammation and implications for treatment of asthma and bronchitis. (1994) in Drugs and the Lung (Advances in Clinical Pharmacology Series) (Page, C. P. and Metzger, W. J., editors), pp. 549-583 (Raven Press, New York).

14.Holtzman, M. J., Zhang, V., Hussain, H., Roswit, W. T., and Wilson, J. D. Prostaglandin H synthase and lipoxygenase gene families in the epithelial cell barrier. (1995) in Cellular generation, transport and effects of eicosanoids: biological roles and pharmacological intervention (Goetzl, E. J., Lewis, R. A., and Rola-Pleszczynski, M., editors), pp. 58-77 (Ann. N. Y. Acad. Sci., New York).

15.Holtzman, M. J. Pulmonology, Section Editor (1998) in Principles of Molecular Medicine, (Jameson, J. L., editor), (Humana Press, Totawa, NJ), pp. 319-327.

16.Holtzman, M. J., Look, D. C., Iademarco, M. F., Dean, D. C., Sampath, D., and Castro, M. Asthma. (1998) in Principles of Molecular Medicine, (Jameson, J. L., editor), (Humana Press, Totawa, NJ), pp. 319-327.

17.Holtzman, M. J., Castro, M., Look, D. C., O'Sullivan, M., Walter, M. J. Regulation of epithelial-leukocyte interaction and epithelial immune-response genes. (2000) in Asthma and Rhinitis, (Busse, W. W. and Holgate, S. T., editors), (Blackwell Scientific, Cambridge, MA), pp. 784-800.

18.Walter, M. J., and Holtzman, M. J. Epithelial production of IL-12 p80 during viral infection and asthma supports an altered paradigm for airway inflammation. (2003) in Lung Biology in Health and Disease: Therapeutic Targets in Airway Inflammation (Eissa, N. T., Huston, D. P., editors), (Marcel Dekker, New York), pp. 535-561.

19.Holtzman, M. J., Kim, E. Y., and Morton, J. D. Genetic and genomic approaches to complex lung diseases using mouse models. (2005) in Computational Genetics and Genomics: Tools for Understanding Disease (Peltz, G., editor), Humana Press Inc., Totowa, NJ, Chapter 6, pp. 99-141.

20.Holtzman, M. J. New drugs for asthma. Whats New in Medicine. (2005) ACP Medicine Dale, D.C., Federman, D.D., Eds..WebMD Inc., New York, p. 1.

21.Battaile, J. T., and Holtzman, M. J. Update on influenza: the Bird Flu threat. Whats New in Medicine. (2006) ACP Medicine Dale, D.C., Federman, D.D., Eds..WebMD Inc., New York, p. 1.

22.Grayson, M. H., and Holtzman, M. J. Asthma. (2007) In ACP Medicine, (Dale, D. C., editor), WebMD Publishing, New York, NY, Chapter 217, in press.

23.Battaile, J. T., and Holtzman, M. J. Update on asthma: Are NKT cells another piece of the asthma puzzle? Whats New in Medicine. (2007) ACP Medicine Dale, D.C., Federman, D.D., Eds..WebMD Inc., New York, p. 1.