Torrey Pines Institute for Molecular Studies science image
Torrey Pines Institute for
Molecular Studies
3550 General Atomics Court, 2-129
San Diego, CA 92121-1122
USA
Scientists
Tony Hugli
Adjunct Member
Protein Chemistry

858.455.3982 - phone
858.455.3804 - fax

Mechanisms of Shock

The aim of our research is to identify the various mediators that induce systemic shock phenomena. There are several conditions that result in shock phenomena including traumatic injury, severe bleeding and/or bacterial infections (i.e. septic shock). It has recently been hypothesized that white cell activation is a major contributor to shock by releasing oxygen radicals, granular enzymes and inflammatory mediators that can injure endothelial cells and enhance vascular permeability and leakage (1, 2). Another conceptual advance in understanding the dynamic processes in shock is the hypothesis of self-digestion of ischemic tissue that results from having protective barriers damaged or eliminated during anoxia (3, 4).

We have shown that there are two major categories of inflammatory mediators in shock (5). One category is the bioactive lipids (platelet activating factor (PAF), leukotrienes (LTC and LTD), various prostaglandins, and membrane lytic lipids such as lysolecithin. The other newly discovered category is bioactive peptides that are released from the ischemic tissue by proteolytic enzymes.

Two of the major organs containing high levels of proteolytic enzymes are the pancreas and the intestines. Therefore, supernatant obtained from homogenates of either of these organs can produce lethal shock in experimental animals. We have separated the lipid fraction from the peptide fraction from pancreatic supernatants and shown that both fractions are able to induce a lethal shock-like response in rats. Our current efforts are to isolate and characterize specific peptides from these peptide mixtures isolated from the pancreatic supernatant. Some of these isolated peptides are presumed to be active shock factors and could be used to understand their mechanisms of action on vascular tissue. Other peptides may be inactive but could serve as antigens for developing immunoassays to monitor the level of ‘shock’ factors in the blood and help predict both the extent and course of potentially lethal shock phenonmena.

Animal Model Development for Preventing Lethal Shock

A miniature pig model has been developed in collaboration with colleagues at UCSD Medical Center to evaluate various treatment modes for hemorrhagic shock.  Our hypothesis is that the gut harbors a high concentration of hydrolytic enzymes and so the intestinal tissue may supply a sizeable quantity of the inflammatory mediators that affect the vascular injury and result in edema or fluid leakage into the tissues. 

These pigs are bled until acute physiologic shock occurs and then the intestine is flushed with fluid containing a proteinase inhibitor called Futhan (nafamostat) (6). The inhibitor is used to prevent the enzymatic attack of the ischemic tissue by the pancreatic enzymes in the lumen of the gut. This strategy is used to prevent the lethal shock response caused by acute hemorrhage and hopefully accomplish survival of the animal.

If the strategy of introducing proteinase inhibitors directly into the intestines, to prevent lethal levels of inflammatory mediators from being formed, proves successful in the animal model, a human protocol could be designed. Since it is proposed that the inflammatory mediators are distributed systemically during reperfusion and their generation continues as long as the tissues are ischemic, inhibition of the enzymes producing the mediators may be effective. The advantage of this model is that the treatment may be effectively applied even after the injury has occurred or the shock response is initiated. A post-injury treatment mode should offer a level of protection for victims of potentially lethal shock and enhance the survival rate for this most acute of all clinical conditions.

Key References. 1-6

  1. Kistler, EB, Hugli, TE, Schmid-Schoenbein GW. The Pancreas as a Source of Cardiovascular Cell Activation Factors. Microcirculation  2000; 7: 183-192.
  2. Schmid-Schoenbein, GW, Kistler, EB, Hugli, TE. Mechanisms for Cell Activation and its Consequences for Biorheology and Microcirculation: Multi-organ Failure in Shock. Biorheology 2001; 38: 185-201.
  3. Fitzal, F, Kistler, EB, Mitsuoka, H., Hugli, TE, Schmid-Schoenbein, GW. A New Hypothesis for the Origin of Shock: Self-Digestion of the Ischemic Intestine by Pancreatic Enzymes. Progress in Inflammation  2005, in press. (a review)
  4. Schmid-Schoenbein, GW and Hugli, TE. Analysis of Trigger Mechanisms for Inflammation in Cardiovascular Diseases: Application to Shock and Multi-Organ Failure. Microcirculation 2005, in press.
    (a review)
  5. Kramp, WJ, Waldo, S., Schmid-Schoenbein, GW, Hoyt, D., Coimbra, R, Hugli, TE. Characterization of Two Classes of Pancreatic Shock Factors: Differences Exhibited by Hydrophilic and Hydrophobic Shock Factors. Shock 2003; 20: 356-362.
  6. Doucet, JJ, Hoyt, DB, Coimbra, R., Schmid-Schoenbein, GW, Junger, WG, Wolf, PL, Loomis, WH, Hugli, TE. Inhibition of Enteral Enzymes by Enteroclysis with Nafamostat Reduces Neutrophil Activation and Transfusion Requirements Following Hemorrhagic Shock. Trauma 2004; 56: 501-512.

Publications

  1. Acosta, J.A., Hoyt, D.B., Schmid-Schoenbein, G.W., Hugli, T.E., Anjaria, D.J., Frankel. D.A., Coimbra, R. Intra-luminal pancreatic serine protease activity, mucosal permeability and shock: A review. Shock 26(1): 3-9, 2006.
  2. Abe, M., Hama, H., Shirakusa, T., Iwasaki, A., Ono, N., Kimura, N., Hugli, T., Okada, N., Katsuragi, T., Okada, H. Contribution of anaphylatoxins to allergic inflamation in human lungs. Microbiol. Immunol. 49:981-986, 2005.
  3. Schmid-Shoenbein, G.W., Hugli, T.E. A new hypothesis for microvascular inflammation in shock and multiorgan failure: self-digestion by pancreatic enzymes. Microcirculation 12:71-82, 2005.
  4. Kramp, W.J., Waldo, S., Schmid-Schoenbein, G.W., Hoyt, D., Coimbra, R., Hugli, T.E. Characterization of two classes of pancreatic shock factors: functional differences exhibited by hydrophilic and hydrophobic shock factors. Shock 20: 356-362, 2003.
  5. Hayashi, J., Salomon, D.R., Hugli, T.E. Elevated kallikrein activity in plasma from stable liver transplant recipients. Int. Immunopharmacol. 2: 1667-1680, 2002.
  6. Jagels, M.A., Daffern, P.J., Hugli, T.E. C3a and C5a enhance granulocyte adhesion to endothelial and epithelial cell monolayers: Epithelial and endothelial priming is required for C3a-induced eosinophil adhesion. Immunopharmacology 46/3:209-222, 2000.
  7. Jagels, M.A., Hugli, T.E. Mixed effects of TGF-b on human airway epithelial-cell chemokine responses. Immunopharmacology 48: 17-26, 2000.
  8. Kistler, E.B., Hugli, T.E., Schmid-Shoenbein, G.W. The pancreas as a source of cardiovascular cell activation factors. Microcirculation 7:183-192, 2000.
  9. Kistler, E.B., Lefer, A.M., Hugli, T.E., Schmid-Schoenbein, G.W. Plasma activation during splanchnic arterial occlusion shock. Shock 14: 30-34, 2000.
  10. Kodani, M., Sakata, N., Takano, Y., Kamiya, H., Katsuragi, T., Hugli, T.E., Abe, M. Intratracheal administration of anaphylatoxin C5a potentiates: Antigen-induced pulmonary reactions through the prolonged production of cysteinyl-leukotrienes. Immunopharmacology 49: 263-274, 2000.
  11. Pfeifer, P.H., Brems, J.J., Brunson, M., Hugli, T.E. Plasma C3a and C4a levels in liver transplant recipients: A longitudinal study. Immunopharmacology 46:163-174, 2000.
  12. Tsuji, R.F., Kawikova, I., Ramabhadran, R., Akahira-Azuma, M., Taub, D., Hugli, T.E., Gerard, C., Askenase, P.W. Early local generation of C5a initiates the elicitation of contact sensitivity by leading to early T cell recruitment. J. Immunol. 165: 1588-1598, 2000.
  13. Askenase, P.W., Kawikova, I., Paliwal, V., Akahira-Azuma, M., Gerard, C., Hugli, T.E., Tsuji R. A new paradigm of T-cell allergy: Requirement for the B-1 cell subset. International Arch. Allergy Immunol. 118:145-149, 1999.
  14. Chao, T.-H., Ember, J.A., Wang, M., Bayon, Y., Hugli, T.E., Ye, R.D. Role of the second extracellular loop of human C3a receptor in agonist binding and receptor function. J. Biol. Chem. 274:9721-9728, 1999.
  15. Daffern, P.J., Jagels, M.A., Hugli, T.E. Multiple Epithelial Cell-Derived Factors Enhance Neutrophil Survival: Regulation by Glucocorticoids and TNF-a. AJRCMB 21: 259-267, 1999.
  16. Daffern, P.J., Jagels, M.A., Saad, J.J., Fischer, W., Hugli, T.E. Upper and lower airway epithelial cells support eosinophil survival in vitro through production of GM-CSF: Regulation by glucocorticoids and TNF-a. Allergy Asthma Proc. 20:243-253, 1999.
  17. Daffern, P.J., Muilenberg, D., Hugli, T.E., Stevenson, D.D. Urinary excretion of leukotriene E4 excretion during aspirin challenge with severity of respiratory responses. J. Allergy & Clin. Immunol. 104:559-564, 1999.
  18. Fischer, W.H., Jagels, M.A., Hugli, T.E. Regulation of IL-6 synthesis in human peripheral blood mononuclear cells by C3a and C3adesArg. J. Immunology 162:453-459, 1999.
  19. Fukuoka, Y., Ember, J.A., Hugli, T.E. Ligand binding sites on guinea pig C3aR: Point- and deletion mutations in the large extracellular loop and vicinity. Biochem. Biophysic. Res. Commun. 263:357-360, 1999.
  20. Jagels, M.A., Daffern, P.J., Zuraw, B.L., Hugli, T.E. Mechanisms and regulation of PMN and eosinophil adherence to human airway epithelial cells. Am. J. Respir. Cell. Mol. Biol. 21:418-427, 1999.
  21. Pfiefer, P.H., Kawahara, M.S., Hugli, T.E. Possible Mechanism for in vitro complement activation in blood and plasma samples: Futhan/EDTA controls in vitro complement activation. Clinical Chem. 45(8 Pt 1):1190-1199, 1999.
  22. Sun, J., Ember, J.A., Chao, Ta.-H., Fukuoka, Y., Ye, R.D., Hugli, T.E. Identification of ligand effector binding sites in transmembrane regions of the human G-protein-coupled C3a receptor. Protein Sci. 8:2304-2311, 1999.
  23. Carney, D.F., Jagels, M.A., Hugli, T.E., Sands, H., Rubin, H. Effect of serine proteinase inhibitors on neutrophil function: alpha-1-proteinase inhibitor, antichymotrypsin, and a recombinant hybrid mutant of antichymotrypsin (LEX32) modulate neutrophil adhesion interactions. J. Leukocyte Biology 63:75-82, 1998.
  24. Ember, J.A., Jagels, M.A., Hugli, T.E. Characterization of complement activation factors: (anaphylatoxins) and their biological responses. In: The human complement system in health and disease, edited by Volanakis, J., Frank, M. New York: Marcel Dekker, Inc., Chapter 11, pp. 241-284, 1998.
  25. Fukuoka, Y., Ember, J.A., Hugli, T.E. Cloning and characterization of rat C3a receptor: Differential expression of rat C3a and C5a receptors by LPS stimulation. Biochem. Biophysic. Res. Commun. 242:663-668, 1998.
  26. Fukuoka, Y., Ember, J.A., Hugli, T.E. Molecular cloning of two isoforms of the guinea pig C3a anaphylatoxin receptor: Alternative splicing at the large extracellular loop. J. Immunol. 161:2977-2984, 1998.
  27. Fukuoka, Y., Ember, J.A., Yasui, A., Hugli, T.E. Cloning and characterization of the guinea pig C5a anaphylatoxin receptor: Interspecies diversity among the C5a receptors. Int. Immunol. 10:275-283, 1998.
  28. Hetland, G., Pfeifer, P.H., Hugli, T.E. Processing of C5a by human polymorpho-nuclear leukocytes. J. Leukocyte Biology. 63 :456-462, 1998.
  29. Mainwaring, R.D., Lamberti, J.J., Hugli, T.E. Complement and cytokine activation following modified fontan procedure. The Annals of Thoracic Surgery 65:1715-20, 1998.
  30. Nakashima, K., Sakurada, T., Imayama, S., Masukawa, S., Ember, J.A., Hugli, T.E., Abe, M. A case of episodic angioedema associated with blood eosinophilia: upregulated C5a receptor expression on eosinophils. Allergy 53 :320-323, 1998.
  31. Akatsu, H., Miwa, T., Sakurada, C., Fukuoka, Y., Ember, J.A., Yamamoto, T., Hugli, T.E., Okada, H. cDNA cloning and characterization of rat C5a anaphylatoxin receptor. Microbiol. Immunol. 41:575-580, 1997.
  32. Ames, R.S., Tornetta, M.A., Foley, J.J., Hugli, T.E., Sarau, H.M. Evidence that the receptor for C4a is distinct from the C3a receptor. Immunopharmacology 38 (1-2): 87-92, 1997.
  33. Ember, J.A., Hugli, T.E. Complement factors and their receptors. In: Special Issue on Complement and Disease. Ed(s). Würzner R, Hugli TE., Amsterdam: Elsevier (Introduction: 38:1, 1997) 38: 3-15, 1997.
  34. Fischer, W.H., Hugli, T.E. Regulation of B cell functions by C3a and C3adesArg: Suppression of TNF-alpha, IL-6, and the polyclonal immune response. J. Immunol. 159 (9) 4279-4286, 1997.
  35. Hsu, M.H., Ember, J.A., Wang, M., Prossnitz, E.R., Hugli, T.E., Ye, R.D. Cloning and functional characterization of the mouse C3a anaphylatoxin receptor gene. Immunogenetics 47(1):64-72, 1997.
  36. Mulligan, M.S., Schmid, E., Till, G.O., Hugli, T.E., Friedl, H.P., Roth, R.A., Ward, P.A. C5a-dependent upregulation in vivo of lung vascular P-selectin. J. Immunol. 158:1857-1861, 1997.
  37. Pfeifer, P.H., Hugli, T.E., Davie, E.W., Fujikawa, K. Complement activation in EDTA blood/plasma samples may be caused by coagulation proteases. In: Techniques in Protein Chemistry VIII. Ed(s): J.W. Crabb, D.R. Marshak, Academic Press, San Diego, CA, pp. 363-369, 1997.
  38. Schmid, E., Piccolo, M.-T. S., Friedl, H.P., Warner, R.L., Mulligan, M.S., Hugli, T.E., Till, G.O., Ward, P.A. Requirements for C5a in dermal and lung vascular injury following thermal trauma to rat skin. Shock 8:119-124, 1997.
  39. Schmid, E., Warner, R.L., Crouch L.D., Friedl, H.P., Till, G.O., Hugli, T.E., Ward, P.A. Neutrophil chemotactic activity and C5a following systemic activation of complement in rats. Inflammation 21:325-333, 1997.
  40. Tanaka, F., Dannenberg Jr., A.M., Higuchi, K., Nakamura, M., Pula, P.J., Hugli, T.E., DiScipio, R.G., Wagner, J.L., Kreutzer, D.L. Chemotactic factors are continuously released by cultured intact developing and healing skin lesions produced in rabbits by sulfur mustard. Inflammation 21:251-267, 1997.
  41. DiScipio, R., Daffern, P.J., Kawahara, M., Pike, R., Potempa, J., Travis, J., Hugli, T.E. Cleavage of human complement C5 by cysteine proteinases from porphyronmonas (bacteroides) gingivalis. Prior oxidation of C5 augments neutrophil activating capacity in Arg-gingipain and Lys-gingipain digests of C5. Immunology 87:660-667, 1996.
  42. Hetland, G., Hugli, T.E. Effect of 125 I-labeled C5a on U937 cells in vitro: A model for cytotoxicity. Cancer Letters. 110:97-103, 1996.
  43. Hugli, T.E. Complement and Inflammation: Inhibiting complement proteases/factors. In: Trends in Biotechnology (review article), Protease Inhibitors: Novel therapeutic application and development. Publishers: Elsevier Trends Journals, Cambridge, UK. 14(11):409-412, Nov. 1996.
  44. Jagels, M.A., Ember, J.A., Travis, J. Potempa, Pike, R., Hugli, T.E. Cleavage of the human C5a receptor by proteinases derived from Porphyromonas gingivalis. In: Intracellular Protein Catabolism, Editor, S. Bond, K. Suzuki, Plenum Publishers. Chapter 19, pp 155-164, 1996.
  45. Jagels, M.A., Ember, J.A., Travis, J., Potempa, J., Pike, R., Hugli, T.E. The Leukocyte C5a receptor is cleaved by proteinases derived from Porphyromonas gingivalis. Infection & Immunity 64:1984-1991, 1996.
  46. Mulligan, M.S., Schmid, E., Till, G.O., Friedl, H.P., Hugli, T.E., Johnson, K.J., Ward, P.A. Requirement and role of C5a in acute lung inflammatory injury in rats. J. Clin. Invest. 98:503-512, 1996.
  47. Ni, F., Carpenter, K.A., Ripoll, D.R., Hugli, T.E., Sanderson, S.D. Biotechnology Research Institute, National Research Council Canada, Montreal, Quebec. Stabilization of an isolated helical capping box in solution by hydrophobic interactions: evidence from the NMR study of bioactive peptides from the C-terminus of human C5a anaphylatoxin. Biopolymers 38:31-41, 1996.
  48. Buchner, R.R., Hugli, T.E., Ember, J.A., Morgan, E.L. Induction of acute phase protein (APP) synthesis in the human hepatocellular carcinoma cell line HepG2 by human C5a. J. Immunol. 155:308-315, 1995.
  49. Daffern, P.J., Pfeifer, P.H., Ember, J.A., Hugli, T.E. C3a is a chemotaxin for human eosinophils but not for neutrophils. I. C3a stimulation of neutrophils is secondary to eosinophil activation. J. Exp. Med. 181:2119-2127, 1995.
  50. Hetland, G., Guinn, K., Hugli, T.E. Effect of formyl peptide (fMLP)-toxin conjugates on myeloid cancer cell lines in vitro. Intl. J. Immunotherapy 3:85-93, 1995.
  51. Hugli, T.E. Physiologic regulation of C3a anaphylatoxin activity by mast cell chymase. In: Biology of Mast Cell Proteases, Editor, George Caughey, Marcel-Dekker Publishers, NY 6:289-304, 1995.
  52. Reed, S.L., Herdman, D.S., Ember, J.A., Hugli, T.E., Gigli, I. The extracellular neutral cysteine proteinsase of Entamoeba histoltica degrades anaphylatoxins C3a and C5a. J. Immunol. 155:266-274, 1995.
  53. Cui, L., Carney, E.F., Hugli, T.E. Primary structure and functional characterization of rat C5a:An anaphylatoxin with unusually high potency. Protein Science 3:1169-1177, 1994.
  54. Donnelly, T.J., Meade, P., Jagels, M.A., Cryer, H.G., Law, M.M., Hugli, T.E., Shoemaker, W.C., Abraham, E. Cytokine, complement, and endotoxin profiles associated with the development of the adult respiratory distress syndrome after severe injury. Crit. Care Med. 22:(5):768-76, 1994.
  55. Ember, J.A., del Zoppo, G.J., Mori, E., Thomas, W.S., Copeland, B.R., Hugli, T.E. Polymorphonuclear leukocyte behavior in a non-human primate focal ischemia model. J.Cere. Blood. Flow. & Metabolism. 14:1046-1054, 1994.
  56. Ember, J.A., Sanderson, S.D., Hugli, T.E., Morgan, E.L. Induction of interleukin-8 synthesis from monocytes by human C5a anaphylatoxin. Am. J. Path. 144:393-403, 1994.
  57. Hetland, G., del Zoppo, G.J., Mori, E., Thomas, W.S., Hugli, T.E. Uptake of C5a by polymorphonuclear leukocytes (PMN's) after focal cerebral ischemnia: I. Effect of tirilazad mesylate intervention on C5a uptake by PMNs. Immunopharm. 27:191-198, 1994.
  58. Jagels, M.A., Chambers, J.D., Arfors, K.-E., Hugli, T.E. C5a and Tumor Necrosis Factor-induced leukocytosis occurs independently of b integrins and L-selectin. Differential effects on neutrophil adhesion molecule expression in vivo. Blood 85:2900-2909, 1994.
  59. Jagels, M.A., Hugli, T.E. Mechanisms and mediators of neutrophilic leukocytes. Immunopharm. 28:1-18, 1994.
  60. Lotz, M., Villeger, P., Hugli, T.E., Koziol, J., Zuraw, B.L. Interleukin-6 and interstitial cystitis. J. Urol. 152:869-873, 1994.
  61. Meade, P., Shoemaker, W.C., Donnelly, T.J., Abraham, E., Jagels, M.A., Cryer, H.G., Hugli, T.E., Bishop, T.E., Wo, C.C. Temporal patterns of hemodynamics, oxygen transport, cytokine activity, and complement activity in the development of adult respiratory distress syndrome after severe injury. J. Trauma 36(5): 651-657, 1994.
  62. Mousli, M., Hugli, T.E., Landry, Y., Bronner, C. Peptidergic pathway in human skin and rat peritoneal mast cell activation. Immunopharm. 27:1-11, 1994.
  63. Zuraw, B.L., Sugimoto, S., Parsons, C.L., Hugli, T.E., Lotz, M., Koziol, J. Activation of urinary kallikrein in patients with interstitial cystitis. J. Urol. 152:874-878, 1994.
  64. Carney, D.F., Hugli, T.E. Site-specific mutations in the N-terminal region of human C5a that affect interactions of C5a with the neutrophil C5a receptor. Protein Science 2:1391-1399, 1993.
  65. Coto, E., Hugli, T.E., Ye, R.D., DiScipio, R.G. A preparation of phage DNA based on affinity chromatograph. Notes & Tips: Analytical Biochemistry 209:199-201, 1993.
  66. Morgan, E.L., Ember, J.A., Sanderson, S., Scholz, W., Buchner, R., Ye, R.D., Hugli, T.E. Anti-C5a receptor antibodies. I. Characterization of neutralizing antibodies specific for the human C5a receptor. J. Immunol. 151:377-388, 1993.
  67. Ember, J.A., Sanderson, D.G., Taylor, S., Kawahara, M., Hugli, T.E. Biologic activity of synthetic analogs of C5a anaphylatoxin. J.Immunol. 148:3165-3173, 1992.
  68. Hugli, T.E. Anaphylatoxins. In: Encyclopedia of Immunology, Saunders Scientific Publications, London, 63-67, 1992.
  69. Jagels, M.A., Hugli, T.E. Neutrophil chemotactic factors promote leukocytosis: A common mechanism for recruitment from bone marrow. J.Immunol. 148:1119-1128, 1992.
  70. Kinoshita, C.M., Gewurz, A., Siegel, J.N., Ying, S.-C., Hugli, T.E., Coe, J.E., Gupta, R.K., Huckman, R,, Gewurz, H. A protease-sensitive site in the proposed Ca2+-binding region of human serum amyloid P component and other pentraxins. Protein Science 1 #6:700-709, 1992.
  71. Mathews, K.P., Mentyka, R.A., Chambers, S.L., Hugli, T.E., Herschbach, J.H., Zuraw, B.L. Cold-dependent activation of complement: Recognition assessment and mechanism. J. Clin. Invest. 12:362-370, 1992.
  72. Morgan, E.L., Sanderson, S.D., Scholz, W., Noonan, D.J., Weigle, W.O., Hugli, T.E. Identification and characterization of the effector region within human C5a responsible for stimulation of interleukin-6 synthesis. J.Immunol. 148:3937-3942, 1992.
  73. Mousli, M., Hugli, T.E., Landry, Y., Bronner, C. A mechanism for anaphylatoxin C3a stimulation of mast cells. J.Immunol. 148:2456-2461, 1992.
  74. Tsai, W.-M., Roos, G., Hugli, T.E., Tan, E.M. Influence of free thiol(s) group on autoantibody-defined epitope of proliferating cell nuclear antigen (PCNA). J.Immunol. 149:2227-2233, 1992.
  75. Wingrove, J.A., DiScipio, R.D., Chen, Z., Potempa, J., Travis, J., Hugli, T.E. Activation of complement components C3 and C5 by a cysteine proteinase (gingipain) from porphyromonas (bacteroides) gingivalis. J.Biol. Chem. 267:18902-18907, 1992.
  76. Ember, J.A., Johansen, M.L., Hugli, T.E. Designing synthetic supra-agonists of C3a anaphylatoxin. Biochemistry 30:3603-3612, 1991.
  77. Kajita, T., Hugli, T.E. Evidence for in vivo degradation of C3a anaphylatoxin by mast cell chymase: I. Non-specific activiation of rat peritoneal mast cells by C3ades Arg. Amer. J. Path. 138:1359-1369, 1991.
  78. Ember, J.A., Johansen, N.L., Hugli, T.E. A new approach to designing active analogues of proteins. Biochem. Soc. Trans. 18:1143-1145, 1990.
  79. Fukuoka, Y., Hugli, T.E. Anaphylatoxin binding and degradation by rat peritoneal mast cells. J. Immunol. 145:1851-1858, 1990.
  80. Hugli, T.E. Complement factors: Their detection and significance. 6th Annual Meeting of the Academy of Allergy & Immunology Workshop. March 23-28, Baltimore, Maryland, 1990.
  81. Kajita T, Hugli, T.E. C5a induced neutrophilia: A primary humoral mechanism for recruitment of neutrophils. Amer. J. Path. 37:467-477, 1990.
  82. Marceau, F., deBlois, D., Laplante, C., Petitclerc, E., Pelletier, G., Hugli, T.E. Contractile effect of the chemotactic factors f-Met-Leu-Phe and C5a on human isolated umbilical artery: Role of cyclo-oxygenase products and tissue macrophages. Circulation Research 67:1059-1070, 1990.
  83. Scholz, W., McClurg, M.R., Cardenas, G.J., Smith, M., Noonan, D.J., Hugli, T.E., Morgan, E.L. C5a-mediated release of interleukin 6 by human monocytes. Clinical Immunol. & Immunopath. 57:297-307, 1990.
  84. Biesecker, G., Wagner, J.L., Hugli, T.E. The release of C5a in complement-activated serum does not require C6. J. Immunol. 143:128-1232, 1989.
  85. DiScipio, R.G., Hugli, T.E. The molecular architecture of human complement component C6. J. Biol. Chem. 264:16197-16206, 1989.
  86. Ember, J.A., Hugli, T.E. Characterization of the human neutrophil response to sex pheromones from Streptococcus Faecalis. Amer. J. Path. 134:797-806, 1989.
  87. Fukuoka, Y., Nielsen, L.P., Hugli, T.E. Characterization of receptors to the anaphylatoxins on isolated cells. Dermatologia 179 (suppl 1):35-40, 1989.
  88. Ganu, V.S., Muller-Eberhard, H.J., Hugli, T.E. Factor C3f is a spasmogenic fragment released from C3b by factors I and H: The heptadeca-peptide C3f was synthesized and characterized. Molecular Immunol. 26:939-948, 1989.
  89. Hugli, T.E. Structure and function of C3a anaphylatoxin. In: Current Topics in Microbiology and Immunology, Volume 153, Component of Complement (John D. Lambris, Hans J. Muller-Eberhard, editors), Springer-Verlag, Berlin-Heidelberg, pgs. 181-208, 1989.
  90. Hugli, T.E. Chemotaxis. In: Current Opinion in Immunology. Jonathan Bond, Editor, Current Science Ltd., London, 2:19-27, 1989.
  91. Kinoshita, C.M., Ying, S.C., Hugli, T.E., Siegel, J.N., Potempa, L.A., Jiang, H., Houghten, R.A., Gewurz, H. Elucidation of a protease-sensitive site involved in the binding of calcium to C-reactive protein. Biochemistry 28:9840-9848, 1989.
  92. Smedegard, G., Cui, L.-X., Hugli, T.E. Endotoxin induced shock in the rat. Role of C5a. Amer. J. Path. 135:489-497, 1989.
  93. Abe, M., Hugli, T.E. Characterization of leukotriene C4 synthetase in mouse peritoneal exudate cells. BBA 959:386-398, 1988.
  94. Chazin, W.J., Hugli, T.E., Wright, P.E. 1H NMR studies of human C3a anaphylatoxin in solution: Sequential resonance assignments, secondary structure and global folding. Biochemistry 27:9139-9148, 1988.
  95. Cui, L.-X., Ferreri K, Hugli, T.E. Structural characterization of the C4a anaphylatoxin from rat. Mol. Immunol. 25:663-671, 1988.
  96. Fukuoka, Y., Hugli, T.E. Demonstration of the specific C3a receptors on guinea pig platelets. J. Immunol. 140:3496-3501, 1988.
  97. Howard, R.J., Crain, C., Franzini, D.A., Hood, I., Hugli, T.E. Effects of cardiopulmonary bypass on pulmonary leukostasis and complement activation. Arch. Surg. 123:1496-1501, 1988.
  98. Lundberg, C., Gardinali, M., Marceau, F., Hugli, T.E. Effect of the anaphylatoxins on vascular tissue in vivo and in vitro. In: CRC Endothelial Cells Volume II, (Editor, Una Ryan) CRC Press, Inc., Boca Raton, Florida , pp. 243-251, 1988.
  99. Clancy, R.M., Dahinden, C.A., Hugli, T.E. Effect of structural modification at carbon atom l of leukotrienes B4 on the chemotactic and metabolic responses of human neutrophils. Anal. Biochem. l6l:550-558, 1987.
  100. Gardinali, M., Cicardi, M., Agostoni, A., Hugli, T.E. Complement activation in extracorporeal circulation. Physiological and pathological implications. Pathol. Immunopathol. Res. 5:352-370, 1987.
  101. Huey, R., Hugli, T.E. Characterization of the chemotactic C5a receptor on human neutrophils. In: Methods in Enzymology, Vol. 150, Section III Chapter 49, (Ed., Giovanni DiSabato, Academic Press), pp. 615-627, 1987.
  102. Hugli, T.E., Marceau, F., Lundberg, C. Effects of complement fragments on pulmonary and vascular smooth muscle. American Respiratory Diseases, l35:S9-Sl3, 1987.
  103. Lundberg, C., Gardinali, M., Hugli, T.E. Complement activation and membrane lipids in lung vascular injury. Amer. Rev. Respir. Dis. 136:459-462, 1987.
  104. Lundberg, C., Marceau, F., Hugli, T.E. C5a-induced hemodynamic and hematologic changes in the rabbit. Role of cyclo-oxygenase products and polymorphonuclear leukocytes. Amer. J. Pathol. 128:471-483, 1987.
  105. Marceau, F., Lundberg, C., Hugli, T.E. Effect of the anaphylatoxins on circulation. (Short Review). Immunopharmacology, 14:67-84, 1987.
  106. Mathews, K.P., Curd, J.G., Hugli, T.E. Decreased synthesis of serum carboxypeptidase N (SCPN) in familial SCPN deficiency. J. Clin. Immunol. 6:87-9l, 1986.
  107. Gardinali, M., Hugli, T.E., Ward, D.M., Agostoni, A. PMN C5a-receptor down regulation is not involved in recovery from C5a-induced neutropenia. ASAIO 10 #3: 482-488, 1986
  108. Gervasoni, Jr., J. E., Conrad, D.H., Hugli, T.E., Schwartz, L.B., Ruddy, S. Degradation of human anaphylatoxin C3a by rat peritoneal mast cells: A role for the secretory granule enzyme and heparin proteoglycan. J. Immunol. l36:285-292, 1986.
  109. Hoeprich, P.D., Hugli, T.E. Helical conformation of carboxyl terminus of human C3a is required for full activity. Biochemistry, 25:1945-1950, 1986.
  110. Huey, R., Fukuoka, Y., Hoeprich, P.D., Hugli, T.E. Cellular receptors to the anaphylatoxins C3a and C5a. In: Biochemical Society Symposium 51:69-81, 1986
  111. Huey, R., Hugli, T.E. Mechanisms of anaphylatoxin-induced inflam­matory reactions. Fifth International Congress of Immunology, Kyoto, Japan, August 21-27, 1983, Academic Press Japan, Inc. In: Chemical Mediators of Inflammation and Immunity, 85-100, 1986
  112. Hugli, T.E. Biochemistry and biology of anaphylatoxins. Complement 3:111-127, 1986.
  113. Lundberg, C., Marceau, F., Huey, R., Hugli, T.E. Anaphylatoxin C5a fails to promote prostacyclin release from cultured human umbilical endothelial cells. Immunopharmacology 12:l35-l43, 1986.
  114. Pelayo, J.C., Chenoweth, D.E., Hugli, T.E., Wilson, C.B., Blantz, R.C. Effects of the anaphylatoxin C5a on renal and glomerular hemodyamics in the rat. Kidney Intl. 30:62-67, 1986.
  115. Skidgel, R.A., Kawahara, M.S., Hugli, T.E. Functional significance of the subunits of carboxypeptidase N (kininase I). In: Kinins IV, (Plenum Plublishing Corp., New York, Editors, L. Greenbaum, H. Margolius), Part A373-378, 1986
  116. Bjork, J., Hugli, T.E., Smedegard, G. Microvascular effects of anaphylatoxins C3a and C5a. J. Immunol. l34:11l5-1119, 1985.
  117. Clancy, R.M., Dahinden, C.A., Hugli, T.E. Complement-mediated arachidonate metabolism. Folia A11ergol. Immunol. Clin. 32:311-3l5, 1985.
  118. Clancy, R.M., Hugli, T.E. Role of complement anaphylatoxins in neutrophil arachidonic acid metabolism. In: Leukotrienes in Cardiovascular and Pulmonary Function, Alan R. Liss, Inc., New York, 173-184, 1985.
  119. Dahinden, C.A., Clancy, R.M., Gross, M., Chiller, J.M., Hugli, T.E. Leukotriene C4 production by murine mast cells: Evidence of a role for extracellular leukotriene A4. PNAS, 82:6632-6636, 1985.
  120. DiScipio, R.G., Gehring, M.R., Podack, E.R., Kan, C.C., Hugli, T.E., Fey, G.H. Nucleotide sequences of cDNA and derived amino acid sequence of human complement component C9. PNAS, 8l:7298-7302, 1985.
  121. DiScipio, R.G., Hugli, T.E. The architecture of complement component C9 and poly(C9). J. Biol. Chem. 260:l4802-l4809, 1985.
  122. Fox, R.I., Hugli, T.E., Lanier, L., Morgan, E.L. Salivary gland lymphocytes in primary Sjorgren's Syndrome lack lymphocyte subsets defined by Leu 7 and Leu ll antigens. J. Immunol. l35:207-2l4, 1985.
  123. Gerard, C., Showell, H.J., Hoeprich, P.D., Hugli, T.E., Stimler, N.P. Evidence for a role of the amino terminal region in the biological activity of the classical anaphylatoxin porcine C5a desArg-74. J. Biol. Chem. 260:26l3-26l6, 1985.
  124. Hoeprich, P.D., Dahinden, C.A., Lachmann, P.J., Davis, A.E., Hugli, T.E. A synthetic nonapeptide corresponding to the NH2-terminal sequence of C3d-K causes leukocytosis in rabbits. J. Biol. Chem. 260:2597-2600, 1985.
  125. Huey, R., Bloor, C.M., Hugli, T.E. Effects of human anaphylatoxins on guinea pig atria. Immunopharmacology, 8:l47-l54, 1985.
  126. Huey, R., Hugli, T.E. Characterization of a C5a receptor on human polymorphonuclear leukocytes (PMN). J. Immunol. l35:2063-2068, 1985.
  127. Hugli, T.E. Complement. In: Medical Microbiology: Principles and Concepts. Medical/Nursing Division (Addison Wesley Pub. Co., New York) Section Edition, Chapter 6 pp. 62-78, 1985.
  128. Hugli, T.E., Marceau, F. Effects of the C5a anaphylatoxin and its relationship to cyclo-oxygenase metabolites in rabbit vascular strips. British J. of Pharmac. 84:725-733, 1985.
  129. Kan, C.C., Fukuoka, Y., Hugli, T.E., Fey, G.H. Expression of human C5a in E. Coli. In: Modern Methods in Protein Chemistry (J. L'italien, Ed., Plenum Press, New York) pp. 539-549, 1985.
  130. Morgan, E.L., Thoman, M.L., Hobbs, M.V., Weigle, W.O., Hugli, T.E. Human C3a-mediated suppression of the immune response. II. Suppression of human in vitro polyclonal antibody responses occurs through the generation of nonspecific OKT8+ suppressor T cells. Clinical Immunology and Immunopathology, 37:114-l23, 1985.
  131. Morgan, E.L., Thoman, M.L., Hoeprich, P.D., Hugli, T.E. Bioactive complement fragments in immunoregulation. Immunology Letters 9:207-213, 1985. Presented at Immunobiologics and their application International Congress, April 2l-27, Budapest, Hungary, 1985.
  132. Morgan, E.L., Thoman, M.L., Weigle, W.O., Hugli, T.E. Human C3a-mediated suppression of the immune response. I. Suppression of murine in vitro antibody responses occurs through the generation of nonspecific Lyt-2 suppressor T cell. J. Immunol. l34:5l-57, 1985.
  133. Williams, C.A., Schupf, N., Hugli, T.E. Anaphylatoxin C5a modulation of an alpha-adrenergic receptor system in the rat hypothalamus. J. Neuroimmunology, 9:29-40, 1985.
  134. Clancy, R.M., Dahinden, C.A., Hugli, T.E. Oxidation of leukotrienes at the end: Demonstration of a receptor for 2-hydroxy derivative of leukotriene B4 on human neutrophils and implications for the analysis of leukotriene receptors. Proc. Natl. Acad. Sci. USA, 8l:5729-5733, 1984.
  135. Clancy, R.M., Dahinden, C.A., Hugli, T.E. Complement mediated arachidonate metabolism. In: Progress in Biochemical Pharmacology (S. Karger A.G. Basel, Switzerland. U.S. Italian Symposium on Cyclooxygenase and Lipoxygenase Modulators in Lung Reactivity, April 5-6, 1984, Milan, Italy (Raven Press) 20:120-131, 1984.
  136. Dahinden, C.A., Clancy, R.M., Hugli, T.E. Stereospecificity of leukotriene B4 and structure-function relationships for chemotaxis of human neutrophils. J. Immunol. 133:1477-1482, 1984.
  137. Heideman, M., Hugli, T.E. Anaphylatoxin generation in multisystem organ failure. Journal of Trauma, 24:l038-l043, 1984.
  138. Huey, R., Erickson, B.W., Bloor, C.M., Hugli, T.E. Contraction of guinea pig lung by synthetic oligopeptides related to human C3a. Immunopharmacology, 8:37-45, 1984.
  139. Hugli, T.E. Complement and cellular triggering reactions. Fed. Proc. 43:2540-2542, 1984.
  140. Hugli, T.E. Structure and function of the anaphylatoxins. In: Springer Seminars in Immunopathology, Complement III, Vol. 7, 193-219, 1984.
  141. Hugli, T.E. Biological activities of fragments derived from human complement components. In: Progress in Immunology V. Fifth International Congress of Immunology, Kyoto, Japan, August 21-27, 1983, Academic Press Japan, Inc., Edited by Y. Yamamura, T. Tada, pp. 419-426, 1984.
  142. Hugli, T.E., Morgan, E.L. Mechanisms of leukocyte regulation by complement-derived factors. In: Contemporary Topics in Immunobiology, Ralph Snyderman, Editor, Plenum Publishing Company, New York, Chapter 4, Vol. 14, pp 109-153, 1984.
  143. Lu, Z.X., Fok, K.F., Erickson, B.W., Hugli, T.E. Conformational analysis of COOH-terminal fragments of human C3a: Evidence of ordered conformation in an active monocosapeptide. J. Biol. Chem. 259:7367-7370, 1984.
  144. Marceau, F.M., Hugli, T.E. Effect of C3a and C5a anaphylatoxins on guinea pig isolated blood vessels. J. Pharma. and Exp. Therapeutics, 230:749-754, 1984.
  145. Morgan, E.L., Weigle, W.O., Hugli, T.E. Anaphylatoxin-mediated regulation of human and murine immune responses. Fed. Proc. 43:2543-2547, 1984.
  146. Thoman, M.L., Meuth, J.E., Morgan, E.L., Weigle, W.O., Hugli, T.E. C3d-K, a kallikrein cleavage fragment of iC3b is a potent inhibitor of cellular proliferation. J. Immunol. l33:2629-2633, 1984.
  147. Unson, C.G., Erickson, B.W., Hugli, T.E. Active site of C3a anaphylatoxin: Contributions of the lipophilic and orienting residues. Biochemistry, 23:585-589, 1984.
  148. Wagner, J.L., Hugli, T.E. Radioimmunoassay for anaphylatoxins in biological fluids: A sensitive method for determining complement activation. Anal. Biochem. 136:75-88, 1984.
  149. Wolach, B., Coates, T.D., Hugli, T.E., Baehner, R.L., Boxer, L.A. Plasma lactoferrin reflects granulocyte activation via complement in burn patients. Journal of Lab. and Clinical Med. 103:284-293, 1984.
  150. Clancy, R.M., Dahinden, C.A., Hugli, T.E. Arachidonate metabolism by human polymorphonuclear leukocytes stimulated by N-formyl peptide or C5a is independent of phospholipase activation. PNAS, 80:7200-7204, 1983.
  151. Clancy, R.M., Hugli, T.E. The extraction of leukotrienes (LTC4, LTD4, and LTE4) from tissue fluids: The metabolism of these mediators during IgE-dependent hypersensitivity reaction in lung. Anal. Biochem. 133:30-39, 1983.
  152. Dahinden, C.A., Fehr, J., Hugli, T.E. Role of cell surface contact on the kinetics of superoxide production by granulocytes. J. Clin. Invest. 72:113-l2l, 1983.
  153. DiScipio, R.G., Smith, C.A., Muller-Eberhard, H.J., Hugli, T.E. The activation of human complement component C5 by a fluid phase C5 convertase. J. Biol. Chem. 258:l0629-l0636, 1983.
  154. Huey, R., Bloor, C.M., Kawahara, M.S., Hugli, T.E. Potentiation of the anaphylatoxins in vivo using an inhibitor of serum carboxypeptidase N (SCPN). I. Lethality and effects on pulmonary tissue. Amer. J. Pathol. 112:48-60, 1983.
  155. Hugli, T.E. Actions of the anaphylatoxins on pulmonary tissues. In: Theoretical and Clinical Aspects of Allergic Diseases, Scandia International Symposium (October 12-14, l982) H. Bostrom, N. Youngstedt, Eds., pp. 197-210, 1983.
  156. Hugli, T.E. The chemistry and biology of C3a, C4a and C5a and their effect on cells. John Jacob Abel Symposium, Baltimore, Maryland, June 21-22, 1982. In: Biological Response Mediators and Modulators, J. Thomas August (Ed.), Academic Press 99-116, 1983.
  157. Hugli, T.E., Kawahara, M.S., Unson, C.G., Molinor, R.L., Erickson, B.W. The active site of human C4a anaphylatoxins. Molecular Immunology 20:637-645, 1983.
  158. Meuth, J.L., Morgan, E.L., DiScipio, R.G., Hugli, T.E. Suppression of T lymphocyte functions by human C3 fragments. I. Inhibition of human T cell proliferative responses by a kallikrein cleavage fragment of human iC3b. J. Immunol. 130:2605-2611, 1983.
  159. Morgan, E.L., Thoman, M.L., Weigle, W.O., Hugli, T.E. Anaphylatoxin mediated regulation of the immune response. II. C5a-mediated enhancement of human humoral and T-cell mediated immune responses. J. Immunol. 130:1257-1261, 1983.
  160. Morgan, E.L., Weigle, W.O., Erickson, B.W., Fok, K.F., Hugli, T.E. Suppression of humoral immune responses by synthetic C3a peptides. J. Immunol. 131:2258-2261, 1983.
  161. Schupf, N., Williams, C.A., Cox, J., Hugli, T.E. Psycho-pharmacological activity of anaphylatoxin C3a in rat hypothalamus. Journal of Neuroimmunology, 5:305-3l6, 1983.
  162. Schwartz, L.B., Kawahara, M.S., Hugli, T.E., Vik, D., Fearon, D.T., Austen, K.F. Generation of C3a anaphylatoxin from human C3 by human mast cell tryptase. J. Immunol. 130:1891-1895, 1983.
  163. Stimler, N.P., Bloor, C.M., Hugli, T.E. C3a-induced contraction of guinea pig lung parenchymal: Role of cyclooxygenase metabolites. Immunopharmacology, 5:251-257, 1983.
  164. Stimler, N.P., Bloor, C.M., Hugli, T.E. Immunopharmacology of complement anaphylatoxins in the lung. In: Immunopharmacology of the Lung, Harold H. Newball, Ed., Vol. 19, pp 401-434, 1983.
  165. Weigle, W.O., Goodman, M.G., Morgan, E.L., Hugli, T.E. Regulation of immune response by fragments of the C3 components of complement. In: Springer Seminars in Immunopathology 6:173-194, 1983.
  166. Bach, M.K., Brashler, J.R., Morton, D.R., Steel, L.K., Kaliner, M.A., Hugli, T.E. Formation of leukotrienes C and D and pharmacologic modulation of their synthesis. In: Leukotrienes and Other Lipoxygenase Products (Editors, B. Samuelsson, R. Paoletti, Raven Press, N.Y.) pp. 103-114, 1982.
  167. Biesecker, G., Gerard, C., Hugli, T.E. An amphiphilic structure of the ninth component of human complement. J. Biol. Chem. 257:2584-2590, 1982.
  168. Chenoweth, D.E., Hugli, T.E. Assays for chemotactic factors and anaphylatoxins. In: Immunologic Analysis. Recent Progress in Diagnostic Laboratory Immunology. (Masson Pub., USA) Chapter 22, 227-237, 1982.
  169. Cohen, A.B., Chenoweth, D.E., Hugli, T.E. The release of elastase, myeloperoxidase, and lysozyme from human alveolar macrophages. Amer. Review Respiratory Diseases, 126:241-247, 1982.
  170. DiScipio, R.G., Hugli, T.E. Circular dichroism studies of human factor H: A regulatory component of the complement system. Biochimica and Biophysica Acta 709: 58-64, 1982.
  171. Hugli, T.E. Bioactive factors of the blood complement system. In: Proteins in Biology and Medicine (R.A. Bradshaw, R. L. Hill, J. Tang, editors) Proceedings of P.R.C.-USA Conference in Shanghai, China, Academic Press, pp. 91-117, 1982.
  172. Morgan, E.L., Hugli, T.E., Weigle, W.O. Isolation and identification of a biologically active peptide derived from the CH3 domain of human IgG1. Proc. Natl. Acad. Sci. USA 79:5388-539l, 1982.
  173. Morgan, E.L., Weigle, W.O., Hugli, T.E. Anaphylatoxin-mediated regulation of the immune response. I. C3a-mediated suppression of human and murine humoral immune responses. J. Exp. Med. 155:1412-1426, 1982.
  174. Seltzer, J.M., O’Connor, R.D., Simon, R.A., Hugli, T.E. Histamine contamination of pokeweed mitogen. J. of Immunological Methods, 55:355-360, 1982.
  175. Weigle, W.O., Morgan, E.L., Goodman, M.G., Chenoweth, D.E., Hugli, T.E. Modulation of the immune response by anaphylatoxin in the micro-environment of the interacting cells. Fed. Proc. 41:3099-3l03, 1982.
  176. Chenoweth, D.E., Stewart, R.W., Cooper, S.W., Blackstone, E.H., Kirklin, J.W., Hugli, T.E. Complement activation during cardiopulmonary bypass: Evidence for generation of C3a and C5a anaphylatoxins. N. Engl. J. Med. 304:497-503, 198l.
  177. Erickson, B.W., Fok., K.F., Khan, S.A., Lukas, T.J., Molinar, R.R., Munoz, H.,Prystowsky, M.B., Unson, C.G., Volk-Weiss, J., Hugli, T.E. Synthetic studies of serum complement. In: Peptides: Synthesis Structure-Function, Proceedings of the Seventh American Peptide Symposium, Edited by D.H. Rich, E. Gross, 525-534, 1981.
  178. Gerard, C., Chenoweth, D.E., Hugli, T.E. Response of human neutrophils to C5a: A role for the oligosaccharide moiety of human C5ades Arg-74 but not of C5a in biological activity. J. Immunol. l27:1978-1982, 198l.
  179. Gerard, C., Hugli, T.E. Identification of the classical anaphylatoxin as the des Arg C5a molecule: Evidence of a modulator role for the oligosaccharide unit in human des-Arg74-C5a. Proc. Natl. Acad. Sci. USA 78:l833-l837, 198l.
  180. Gerard, C., Hugli, T.E. C5a: A mediator of chemotaxis and cellular release reactions. Fourth International Symposium on Biochemistry of Acute Allergic Reactions. In: Kroc Symposia Series, Alan R. Liss, Inc., New York, pp. 147-160, 1981.
  181. Gorski, J.P., Hugli, T.E., Muller-Eberhard, H.J. Characterization of human C4a anaphylatoxins. J. Biol. Chem. 256:2707-2711, 198l.
  182. Hugli, T.E. The structural basis for anaphylatoxin in chemotactic functions of C3a and C5a. In: Critical Reviews in Immunology, I, No. 4, CRC Press Review, Boca Raton, FL pp. 321-366, 1981.
  183. Hugli, T.E. Interrelationships between coagulation and complement activation. In: Perspectives in Hemostasis, J. Fareed, H.L. Messore, J.W. Fenton II, K.M. Brinkhous, Eds., Permagon Press, Inc., New York, pp. 59-69, 1981.
  184. Hugli, T.E. The complement anaphylatoxins. In: Topics in Allergology, (T. Hofstaetter, H.U. Schorlemmer, editors) Behring Institute Mitteilungen (BIM) 68:68-81, 1981.
  185. Hugli, T.E., Chenoweth, D.E. Biologically active peptides of complement:Techniques and significance of C3a and C5a measurements. In: Immunoassays:Clinical Laboratory Techniques for the l980s, R.M. Nakamura, W.R., Dito, E.S. Tucker III, Eds., Alan R. Liss, Inc., New York,Vol. 4, pp.443-460, 1981.
  186. Hugli, T.E., Gerard, C., Kawahara, M., Scheetz, M.E., Barton, R., Briggs, S., Koppe, G., Russel, S. Isolation of three separate anaphylatoxins from complement-activated human serum. Molecular and Cellular Biochem. 41:59-66, 1981.
  187. Hugli, T.E., Stimler, N.P., Gerard, C., Moon, K.E. Possible role of serum anaphylatoxins with hypersensitivity reactions. 13th Symposium of the Collegium Internationale Allergologicum, "Cellular Interactions in Allergy", Konstanz, Germany, In: Monographs in Allergy, S. Karger, Ed-in-Chief R.R.A. Coombs, Cambridge.Int. Archs Allergy Appl. Immunol 66 (Supp l) 113-120, 1981.
  188. Meuer, S., Hugli, T.E., Andreatta, R.H., Hadding, U., Bitter-Suerman, D. Comparative study on biological activities of various anaphylatoxins (C4a, C3a, C5a)1/28/2005 Investigations on their ability to induce platelet secretion. Inflammation, 5 (4):263-273, 1981.
  189. Moon, K.E., Gorski, J.P., Hugli, T.E. Complete primary structure of human C4a anaphylatoxin. J. Biol. Chem. 256:8685-8692, 1981.
  190. Stimler, N.P, Bach, M.K., Bloor, C.M., Hugli, T.E. Release of leukotrienes from guinea pig lung stimulated by C5ades Arg anaphylatoxin. J. Immunol. l28:2247-2252, 1982.
  191. Stimler, N.P., Bloor, C.M., Hugli, T.E., Wykle, R.L., McCall, C.E., O'Flaherty, J.T. Anaphylactic actions of platelet activating factor. Am. J. Pathol. l05:64-69, 198l.
  192. Stimler, N.P., Brocklehurst, W.E., Hugli, T.E., Bloor, C.M. Anaphylatoxin mediated contraction of guinea pig lung strips: A non-histamine tissue response. J. Immunol. l26:2258-226l, 198l.
  193. Aronson, D.L., Ball, A.P., Franza, R.B., Hugli, T.E., Fenton II, J.W. Human prothrombin fragments F1 () F2: Preparation and characterization of structural and biological properties. Thromb. Res. 20:239-253, 1980.
  194. Caporale, L.H., Tippett, P.S., Erickson, B.W., Hugli, T.E. The active site of C3a anaphylatoxin. J. Biol. Chem. 255:10758-10763, 1980.
  195. Chenoweth, D.E., Hugli, T.E. Human C5a and C5a analogs as probes of the neutrophil C5a receptor. Mol. Immunol. 17:151-161, 1980.
  196. Chenoweth, D.E., Lane, T.A., Rowe, J.G., Hugli, T.E. Quantitative comparisons of neutrophil chemotaxis in four animal species. Clin. Immunol. Immunopathol. l5:525-535, 1980 (Frank Dixon Festschrift).
  197. Gerard, C., Hugli, T.E. Amino acid sequence of the anaphylatoxin from the fifth component of porcine complement. J. Biol. Chem. 255:4710-4715, 1980.
  198. Goodman, M.G., Weigle, W.E., Hugli, T.E. Inability of the C3a anaphylatoxin to promote cellular lysis. Nature, 283:78-80, 1980.
  199. Mathews, K.P., Pan, P.M., Gardner, N.H., Hugli, T.E. Familial carboxypeptidase N deficiency. Ann. Intern. Med. 93:443-445, 1980.
  200. Sartin, J.L., Hugli, T.E., Liao, T.H. Reactivity of the tryptophan residues in bovine pancreatic deoxyribonuclease with N-bromosuccinimide. J. Biol. Chem. 255:8633-8637, 1980.
  201. Stimler, N.P., Brocklehurst, W.E., Bloor, C.M., Hugli, T.E. Complement anaphylatoxin C5a stimulates release of SRS-A-like activity from guinea pig lung fragments. J. Pharm. Pharmacol. 32:804, 1980.
  202. Stimler, N.P., Hugli, T.E., Bloor, C.M. Pulmonary injury induced by C3a and C5a anaphylatoxins. Am. J. Pathol. l00:327-340, 1980.
  203. Chenoweth, D.E., Erickson, B.W., Hugli, T.E. Human C5a-related synthetic peptides as neutrophil chemotactic factors. Biochem. Biophys. Res. Commun. 86:227-234, 1979.
  204. Chenoweth, D.E., Rowe, J.G., Hugli, T.E. A modified method for chemotaxis under agarose. J. Immunol. Methods, 25:337-353, 1979.
  205. Gerard, C., Chenoweth, D.E., Hugli, T.E. Molecular aspects of the serum chemotactic factors. J. Reticuloendothel. Soc. 26:711-718, 1979 (Pfizer Symposium).
  206. Gerard, C., Hugli, T.E. Anaphylatoxin from the fifth component of porcine complement. I. Purification and partial chemical characterization. J. Biol. Chem. 254:6346-635l, 1979.
  207. Glovsky, M.M., Hugli, T.E., Ishizaka, T., Lichenstein, L.M., Erickson, B.W. Anaphylatoxin-induced histamine release with human leukocytes: Studies of C3a leukocyte binding and histamine release. J. Clin. Invest. 64:804-811, 1979.
  208. Gorski, J.P., Hugli, T.E., Muller-Eberhard, H.J. C4a: The third anaphylatoxin of the human complement system. Proc. Natl. Acad. Sci. USA, 76:5299-5302, 1979.
  209. Harpel, P.C., Hayes, M.B., Hugli, T.E. Heat induced fragmentation of human 2-macroglobulin. J. Biol. Chem. 254:8669-8678, 1979.
  210. Hugli, T.E. Complement anaphylatoxins as plasma mediators, spasmogens and chemotaxins. In: The chemistry and Physiology of Human Plasma Proteins, D.H. Bing, Ed., Pergamon Press, New York pp. 255-280, 1979.
  211. Lesavre, P.H., Hugli, T.E., Esser, A.F., Muller-Eberhard, H.J. The alternative pathway C3/C5 convertase: Chemical basis of Factor B activation. J. Immunol. l23:529-534, 1979.
  212. Unson, C.G., Erickson, B.W., Hugli, T.E. Role of leucine residues in the active site of C3a anaphylatoxin. In: Peptides:Structure and Biological Function. Eds., E. Gross, J. Meinehofer, Rockford, Il, pp. 459-462, 1979.
  213. Ward, P.A., Hugli, T.E., Chenoweth, D.E. Complement and chemotaxis. In: Chemical Messengers of the Inflammatory Process, J. Houck, Ed., Elsevier/North-Holland Biomedical Press B.V., Amsterdam, The Netherlands pp. 153-178, 1979.
  214. Chenoweth, D.E., Hugli, T.E. Demonstration of a specific C5a receptor on intact human polymorphonuclear leukocytes. Proc. Natl. Acad. Sci. USA, 75:3943-3947, 1978.
  215. Fernandez, H.N., Henson, P.M., Otani, A., Hugli, T.E. Chemotactic response to human C3a and C5a anaphylatoxins. I. Evaluation of C3a and C5a leukotaxis in vivo and in vitro. J. Immunol. 120:109-115, 1978.
  216. Fernandez, N.H., Hugli, T.E. Primary structural analysis of the polypeptide portion of human C5a anaphylatoxin. I. Polypeptide sequence determination and assignment of the oligosaccharide attachment site in C5a. J. Biol. Chem. 253:6955-6964, 1978.
  217. Glovsky, M.M., Hugli, T.E., Hartman, C.T., Ghekiere, L. Possible role of C3a in human disease. In: Clinical Aspects of the Complement System, W. Opferkuch, K. Rother, Eds., Pieme Verlag Publishers, Stuttgart, West Germany, pp. 138-144, 1978.
  218. Hugli, T.E. Chemical aspects of the serum anaphylatoxins. In: Comtemporary Topics in Molecular Immunology, 7, R.A. Reisfeld, F. Inman, Eds., Plenum Press, New York, pp. 181-214, 1978.
  219. Hugli, T.E., Muller-Eberhard, H.J. Anaphylatoxins: C3a and C5a. In: Advances in Immunology, 26, H.G. Kunkel, Frank J. Dixon, Ed., Academic Press, New York, pp. 1-53, 1978.
  220. Jacobs, J.W., Rubin, J.S., Hugli, T.E., Bogardt, R.A., Mariz, I.K., Daniels, J.S., Daughaday, W.H., Bradshaw, R.A. Purification, characterization, and amino acid sequence of rat anaphylatoxin (C3a). Biochemistry, 17:5031-5038, 1978.
  221. Caporale, L.H., Erickson, B.W., Hugli, T.E. Synthetic oligopeptides from human C3a anaphylatoxin that mediate the inflammatory response. In: Proceedings of the Fifth American Peptide Symposium, M. Goodman, J. Meienhofer, Ed.Halstead Press, New York , pp. 225-227, 1977.
  222. Fernandez, H.N., Hugli, T.E. Chemical evidence for common genetic ancestry of complement components C3 and C5. J. Biol. Chem. 252:1826-1828, 1977.
  223. Fernandez, H.N., Hugli, T.E. Structural and functional comparison between human C3a and C5a. In: Proceedings of the Fifth American Peptide Symposium, M. Goodman, J. Meienhofer, Eds., Halstead Press, New York , pp. 228-231, 1977.
  224. Goyert, S.M., Hugli, T.E., Spiegelberg. H.L. Sites of "spontaneous" degradation of IgD. J. Immunol. 118:2138-2144, 1977.
  225. Hugli, T.E. Complement factors and inflammation: Effects of alpha-thrombin on components C3 and C5. In: Chemistry and Biology of Thrombin, R.L. Lundblad, J.W. Fenton, K.G. Mann, Eds., Ann Arbor Science Publishers, Inc., Ann Arbor, Michigan pp 46-360, 1977.
  226. Hugli, T.E., Erickson, B.W. Synthetic peptides with the biological activities and specificity of human C3a anaphylatoxin. Proc. Natl. Acad. Sci. USA 74:1826-1830, 1977.
  227. Otani, A., Hugli, T.E. Leukocyte chemotaxis: A new in vitro testing technique. Inflammation, 2:67-82, 1977.
  228. Taylor, J.C., Crawford, I.P., Hugli, T.E. Limited degradation of the third component (C3) of human complement by human leukocyte elastase (HLE): Partial characterization of C3 fragments. Biochemistry, 16:3390-3396, 1977.
  229. Corbin, N.C., Hugli, T.E. The primary structure of porcine C3a anaphylatoxin. J. Immunol. 117:990-995, 1976.
  230. Corbin, N.C., Hugli, T.E., Muller-Eberhard, H.J. Serum carboxypeptidase B: A spectrophotometric assay using protamine as substrate. Anal. Biochem. 73:41-51, 1976.
  231. Fernandez, H.N., Hugli, T.E. Partial characterization of human C5a anaphylatoxin. I. Chemical description of the carbohydrate and polypeptide portions of human C5a. J. Immunol. 117:1688-1694, 1976.
  232. Harpel, P.C., Hugli, T.E., Cooper, N.R. Studies on human plasma C1 inactivator-enzyme interactions. II. Structural features on an abnormal C1 inactivator from a kindred with hereditary angioneurotic edema. J. Clin. Invest. 55:605-611, 1975.
  233. Hugli, T.E. Human anaphylatoxin (C3a) from the third component of complement: Primary structure. J. Biol. Chem. 250:8293-8301, 1975.
  234. Hugli, T.E. Serum Anaphylatoxins: Formation, characterization and control. In: Proteases and Biological Control, E. Reich, D.B. Rifkin, and E. Shaw, Eds., Cold Springs Harbor Laboratory, pp. 273-290, 1975.
  235. Hugli, T.E., Morgan, W.T., Muller-Eberhard, H.J. Circular dichrosim of C3a anaphylatoxin: Effects of pH, heat, guanidinium chloride and mercaptoethanol on conformation and function. J. Biol. Chem. 250:1479-1483, 1975.
  236. Hugli, T.E., Vallota, E.H., Muller-Eberhard, H.J. Purification and partial characterization of human and porcine C3a anaphylatoxin. J. Biol. Chem. 250:1472-1478, 1975.
  237. Johnson, A.R., Hugli, T.E., Muller-Eberhard, H.J. Release of histamine from mast cells by the complement peptides C3a and C5a. Immunology 8:1067-1080, 1975.
  238. Mahler, F., Intaglietta, M., Hugli, T.E., Johnson, A.R. Influences of C3a anaphylatoxin compared to other vasoactive agents on the microcirculation of the rabbit omentum. Microvasc. Res. 9:345-356, 1975.
  239. Revak, S.D., Cochrane, C.G., Johnson, A.R., Hugli, T.E. Structural changes accompanying enzymatic activation of human Hageman factor. J. Clin. Invest. 54:619-627, 1974.
  240. Hugli, T.E. The preparation and characterization of an active derivative of bovine pancreatic deoxyribonuclease A formed by selected cleavage with -chymotrypsin. J. Biol. Chem. 248:1712-1718, 1973.
  241. Hugli, T.E., Bustin, M., Moore, S. Spectrophotometric assay of 2', 3'-cyclic nucleotide-3'-phosphohydrolase: Application to the enzyme in bovine brain. Brain Res. 58:191-203, 1973.
  242. Hugli, T.E., Moore, S. Determination of the tryptophan content of proteins by ion exchange chromatography of alkaline hydrolysates. J. Biol. Chem. 247:2828-2834, 1972.
  243. Hugli, T.E., Stein, W.H. Involvement of a tyrosine reside in the activity of bovine pancreatic deoxyribonuclease A. J. Biol. Chem. 246:7191-7200, 1971.
  244. Hugli, T.E., Gurd, F.R.N. Carboxymethylation of sperm whale myoglobin the crystalline state. J. Biol. Chem. 245:1930-1938, 1970.
  245. Hugli, T.E., Gurd, F.R.N. Carboxymethylation of sperm whale myoglobin in the dissolved state. J. Biol. Chem. 245:1939-1946, 1970.
  246. Wuthrich, K., Shulman, R.G., Yamane, T., Wyluda, B.J., Hugli, T.E., Gurd, F.R.N. High resolution proton magnetic resonance studies of cyanoferrimyoglobin and alkylated derivatives from different species. J. Biol. Chem. 245:1947-1953, 1970.
  247. Gurd, F.R.N., Hugli, T.E., Bradshaw, R.A. Structure and reactivity of myoglobin. Polymer Preprints, p.123, 1969.
  248. Cotman, C.W., Mahler, H., Hugli, T.E. Isolation and characterization of insoluble proteins of the synaptic plasma membrane. Arch. Biochem. Biophy. 126:821-837, 1968.

Patents

  1. Methods for assessing complement activation. U.S. Patent No. 6,297,024. Issued October 2, 2001.   Inventors:  Hugli, T.E., Stoughton, R.B.
  2. Substrates for assessing mannan-binding protein-associated serine protease activity and methods using the substarates. U.S. Patent No. 6,235,494. Issued May 22, 2001.   Inventors:  Hugli, T.E.
  3. Antibodies to human C5a receptor. U.S. Patent No. 5,480,974. Issued January 2, 1996.   Inventors:  Morgan, E.L., Ember, J.A., Hugli, T.E.
  4. Synthetic peptides. U.S. Patent No. 4,438,029. Issued March 20, 1984.  Inventors:  Erickson, B.W., Hugli, T.E.
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