Alfred Ayala, PHD, MS
Professor of Surgery (Research)
Research interests include differential effects of sepsis on immune cell function, the role of programmed cell death/apoptosis in immune dysfunction observed following hemorrhage and/or sepsis, as well as the contribution of the apoptotic process to phagocyte mediated acute lung injury resultant from shock and/or septic insults.
BiographyDr. Ayala is Professor of Surgery (Research) at Rhode Island Hospital/Brown University School of Medicine. He serves/ served as both a standing and an ad hoc member of the National Institutes of Health (NIH) Surgery Anesthesia Trauma (SAT)-Study Section, various NIH site visit teams, served on the Veteran's Administration (VA)-Department of Defense (DoD) Merit Review Board, Wellcome Trust as well as Shriners Hospitals. He has been recognized by his peers through election to President (04'-05'), Treasurer (02'-04'), and Scientific Program Chairman (01) of the Shock Society; as selection as Recorder/Executive Council (05'-07') of the Surgical Infection Society, and by appointment to the Society of Leukocyte Biology council (11'-present). Dr. Ayala was also the recipient of the Shock Society's 10th annual 'Scientific Achievement Award' (07')and the 15th annual 'Distinquished Service Award'. He has over 290 manuscripts/review articles to his credit and has been continuously funded by the NIH since 1991. He is also a member of the training faculty of the Brown University Graduate Pathobiology Program and is and adjunct Professor/mentor in the Univ. R.I. graduate program in the Department of Cellular & Molecular Biology. During his tenure at Brown University and previously at Michigan State University he has had the privilege of mentoring students ranging from undergraduates and medical students to residents and post-doctoral fellows. Dr. Ayala's research interests include differential effects of sepsis on immune cell function; the role of programmed cell death/apoptosis in immune dysfunction observed following hemorrhage and/or sepsis; as well as the contribution of the apoptotic process to phagocyte mediated acute lung injury resultant from shock and/or septic insults.
Research DescriptionThe work in our laboratory has centered on understanding the patho-physiological effects of shock/ tissue injury/ sepsis that lead to immune dysfunction and subsequent multiple organ failure in the critically ill trauma patient (through animal modeling and collaborative clinical studies). We have described, over the years, numerous deficits in both components of cell-mediated (T-cell, NKT-cell, gd T-cell, Treg-cell, etc) and innate (macrophage, neutrophil, dendritic cells) immune responsiveness induced by shock or sepsis, which are underpinned by alterations in cell signaling, protein translation and transcription patterns. Particular emphasis has been directed at defining the role of soluble mediators (e.g., IL-4, IL-10, IL-16, MCP-1, MIP-2/KC/IL-8, TGF-b, PGE2, NO, steroids, etc.), inhibitory receptors (e.g., PD-1:PD-L1/L2, BTLA:HVEM, FasL:Fas, etc.) and/or cellular pathways (e.g., p38 MAPKs, STAT 1/4/6, SOCS 1/3, Shp1/2, Rip1/3, NFkB, etc.) involved in orchestrating these changes in mouse models and critically ill patient. We have also found evidence of alterations of the immune cell's apoptotic process, present in these animals and are actively examining the contribution of this pathway. It is our hope that, by understanding the cellular/molecular mechanisms which control these alterations in the traumatized or septic animal/patient, we will improve our ability to treat them.
Major Theme of Research: Immunology and infection
Laboratory Staff-Contact List (Rev: 3/14/2013):
Maude Kettenmann, M.D.
Armand D. Versaci Res. Scholar/
John Young, M.D.
Armand D. Versaci Res. Scholar/
Lunxian (Kelly) Tang, M.S., M.D.
Visiting Scholar in Surgery
Youping Wu, M.S., M.D.
Research Scholar in Surgery
Noelle A. Hutchins, B.S.
Grad. Student / NRSA pre-doc fellow
(Brown U-Pathobiol. Prog.)
Yaping Chen, B.S.
Sr. Res. Assist.
Courtney V. Coto, A.D. Med. Trans.
Walter Anazonwu, B.A.
Brown U.-Med. Student-Summer Res. Assistantship/Project
Laboratory Alumni (back to: 2000):
Fei Wang, M.D., M.S.
Sam McNeal, Ph.D.
Nicholas Shubin, Ph.D.
Jianwen (Jen) Bai, M.D., M.S.
Gabriela Garcia, B.A.
Lydea Irwin, B.S.
Shivana Maharaj, B.A.
Sean Monaghan, M.D.
Eleanor (Ellie) Smith, B.S.
Ye Sul Kim, B.S.
Yvonne Wang, B.S., M.D.
Yu (Tina) Zhao.
Mia Tran, B.S.
Rajan Thakkar, M.D.
Sima Patel, B.S.
Nicholas Carter, B.A.
Sadella Santos, B.S.
Fabienne Venet, Ph.D., M.S., Pharm.D.
Arnaldo Carriera, B.S.
Ana Moreno, B.S.
Megan Garber, B.S., M.S.
Earl Campbell, III, B.S.
Brian J. Horner, D.O.
Ryan Swan, M.D.
Doreen Wesche-Soldato, Ph.D.
Leia Foster, B.S.
Caroline Hu, B.A., M.S.
Mario Perl, M.D.
Ulrike (Uli) Perl, R.N.
Antonio Funches, B.S.
Tina Rachel, B.A., M.S.
Nicholas Winoski, B.A., M.D.
Ben Galen, B.S., M.D.
Lesley Doughty, M.D.
Rani Cooma-Ramberan, B.S.
Leslie Jones, B.S.
Sarah Newton (maiden name: Bray), B.A., M.D.
Rebecca Rhee, B.A., M.D.
Yanli Ding, D.D.S., Ph.D, D.M.D
Patricia S. Grutkoski, Ph.D.
Crystal Lane, B.S.
Grace Jarrar (maiden name: Song), M.D., B.A.
Watkins, B.A., Ph.D.
Amit R.T. Joshi, M.D., B.A.
Rory A. Priester, M.D., B.A.
Grants and AwardsRecipient of the Shock Society's - Distinguished Service Award (2011)
Recipient of the Shock Society's - Scientific Achievement Award (2007)
Surgical Infection Society - Joseph Susman Awarde (1994)
SIS Recorder/Council Member (2005-07)
Society of Leukocyte Biology- Councilor (2011-present) (by appoinment)
Society of Leukocyte Biology- Co-Program Chariman (2013) (by appoinment)
Shock Society- President (2004-05), Treasurer (2002-04), Sci. Program Chair. (2001)
Society of Leukocyte Biology- Councilor (2011-present) (by appoinment)
AffiliationsAmerican Society of Investigative Pathology
American Association for the Advancement of Science
American Association of Immunologists
International Cytokine Society
Michigan Society for Medical Research
Society of Protozoologists
Surgical Infection Society
Society of Critical Care Medicine
Society of Leukocyte Biology
Funded ResearchActive Grant Support:
NIH-NIHLBI: "Regulatory Mechanisms of Acute Lung Injury: Phagocyte Apoptosis."
Grant No. RO1 HL73525
Principal Investigator: Alfred Ayala
Total Support = $1,542,875 in direct and indirect cost (for 2008-2013).
NIH-NIGMS Research Grant: "Differential Effects of Sepsis on Immune Cell Function."
Grant No. R01 GM46354
Principal Investigator: Alfred Ayala
Total Support = $1,331,926 in direct and indirect cost (for 2009-2012).
NIH-NIGMS Research Grant: "Programmed Cell Death: Role in Septic Immune Suppression."
Grant No. RO1 GM53209
Principal Investigator: Alfred Ayala
Total Support = $1,039,163 in direct and indirect cost (for 2010-2014).
Grants/Funding on which 'role' is other than Principle Investigator:
NIDDK NRSA: "Fatal Attraction: T lymphocytes and liver endothelial cells during sepsis"
Grant No. F31 DK083873
Principle Investigator: Noelle Hutchins
Sponsor: Alfred Ayala
Total Fellowship Support = $163,500 in direct and indirect cost.
NIH-NIGMS: "Trauma-inflammation Research Training."
Grant No.: T32-GM08768
Program Director: Jorge E. Albina
Co-Director/Executive Committee/Faculty: Alfred Ayala
Total Support Requested = $1,158,247 in direct and indirect cost.
NIH-Research Grant: "Neutrophil-Kupffer Cell Interaction during Infection."
Grant No.: R01-DK 61511
Principle Investigator: Stephen H. Gregory
Collaborator: Alfred Ayala
Total Support Requested = ~$1,250,000 in direct and indirect cost.
NIH-NIHLBI: "Short-term Training for Minority Students."
Grant No.: T35-HL67704
Principal Investigator: Sharon I.S. Rounds
Faculty Trainer/Exec. Comm.: Alfred Ayala
Total Support = $229,900 in direct and indirect cost.
Rhode Island Foundation: "Mediators of Endothelial Cell Dysfunction in the Development of Shock Induced Lung Injury."
Grant No.: #20092951
Principal Investigator: Joanne Lomas-Neira
Collaborator: Alfred Ayala
Total Support Requested = $15,000 in direct cost.
- Hutchins, N.A., Chung, C.S., Ayala, C.A., Ayala, A. 2013. Kupffer cells protect sinusoidal endothelial cells from Fas-dependent apoptosis in sepsis by down-regulating gp130. Amer. J. Pathol. 182: 742-54. (PMID: 23306157) (2013)
- Monaghan, S.F., Thakkar, R.K., Tran, M., Huang, X., Cioffi, W.G., Ayala, A., Heffernan, D.S. 2012. PD-1 expression as a marker for immune and physiological dysfunction in the critically ill surgical patient. Shock 38:117-122. (PMID: 22683728) (2012)
- Shubin, N.J., Monaghan, S.F., Heffernan, D., Chung, C.S., Ayala, A. 2012. B and T Lymphocyte Attenuator (BTLA) and the role of lymphocytes in contributing to sepsis progression. J. Leukocyte Biol. (epub-ahead of press). (PMID: 22459947) (2012)
- Heffernan, D.S., Monaghan, S.F., Thakkar, R.K., Machan, J.T., Ayala, A., Cioffi, W.G. 2012. Failure to normalize lymphocyte reduction following trauma is associated with increased mortality, independent of the leukocytosis pattern. Critical Care Forum 16(1):R12. (PMID: 22264310) (2012)
- Monaghan, S.F., Thakkar, R.K., Heffernan, D.S., Tran, M.L., Huang, X., Chung, C.S., Chen, Y., Lomas-Neira, J., Cioffi, W.G., Ayala, A. 2012. Mechanisms of indirect acute lung injury: a novel role for the co-inhibitory receptor, programmed death-1 (PD-1). Ann. Surg. 255:158-64. (PMID: 21997806) (2012)
- Lomas-Neira, J., Perl, M., Venet, F., Chung, C.S., Ayala, A. 2012. The Role and Source of TNF-α in Hemorrhage Induced Priming for Septic Lung Injury. Shock 37:611-20. (PMID: 22552013) (2012)
- Shubin, N., Monaghan, S., Ayala, A. 2011. Anti-inflammatory mechanisms in sepsis. Contrib. Microbiol. 17:108-124 . (REVIEW; PMID: 21659749). (2011)
- Guignant, C., Lepape, A., Huang, X., Kherouf, H., Denis, L., Poitevin, F., Malcus, C., Chéron, A., Allaouchiche, B., Gueyffier, F., Ayala, A., Monneret, G., Venet, F. 2011. Programmed Death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit. Care Forum 15:R99. (PMID: 21418617). (2011)
- McNeal, S.I., LeGolvan, M.P., Chung, C.S., Ayala, A. 2011. Dual functions of RIP1 in Fas induced hepatocyte death during sepsis. Shock 35:499-505. (PMID: 21263386). (2011)
- Venet, F., Huang, X., Chung, C.S., Chen, Y., Ayala, A. 2010. Plasmacytoid dendritic cells control lung inflammation and monocyte recruitment in indirect acute lung injury in mice. Amer. J. Pathol. 176:764-73. (PMID: 20042672). (2010)
- Chung, C.S., Venet, F., Chen, Y., Jones, L., Wilson, D., Ayala, C.A., Ayala, A. 2010. Deficiency of BID protein reduces sepsis-induced apoptosis and inflammation, while improving septic survival. Shock 33:150-61. (PMID: 20023601). (2010)
- Perl, M., Chung, C.S., Perl, U., Thakkar, R., Lomas-Neira, J., Ayala, A. 2010. Therapeutic accessibility of caspase mediated cell death as a key patho-mechanism in indirect acute lung injury. Crit. Care. Med. 39:1179-86. (PMID: 0154604). (2010)
- Stromberg, P., Woolsey, C., Clark, A., Clark, J., Turnbull, I., McConnell, K., Chang, K., Chung, C-S., Ayala, A., Buchman, T., Hotchkiss, R.S., Coopersmith, C. 2009. CD4+ lymphocytes control gut epithelial apoptosis and mediate survival in sepsis. FASEB J. 23:1817-1825 (PMID: 19158156) (2009)
- Huang, X., Venet, F., Wang, Y.L., Lepape, A., Yuan, Z., Wang, Y.L., Chen, Y., Swan, R., Kherouf, H., Monneret, G., Chung, C.S., Ayala, A. 2009. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc. Natl. Acad. Sci. U.S.A. 106:6303-6308 (PMID: 19332785) (2009)
- Elphick, G., Sarangi, P., Hyun, Y-M., Hollenbaugh, J., Ayala, A., Biffl, W., Chung, H-L., Rezaie, A., McGarth, J., Topham, D., Reichner, J., Kim, M. 2009. Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood 113:4078-4085. (PMID: 19244161) (2009)
- Hu, C.*, Venet, F.*, Heffernan, D.S., Wang, Y., Horner, B., Huang, X., Chung, C.S., Gregory, S.H., Ayala, A. 2009. The role of hepatic invariant (i)NKT cells in systemic/ local inflammation and mortality during polymicrobial septic shock? J. Immunology 182(4):2467-75.(*C.K.H and F.V. contributed equally as first authors to this work) (PMID: 19201902). (2009)
- Fritzell, Jr., J.A., Mao, Q, Gundavarapu, S., Pasquariello, T., Aliotta, J., Ayala, A., Padbury, J.F., De Paepe, M.E. 2009. Fate and effects of adult bone marrow cells in lungs of normoxic and hyperoxic newborn mice. Amer. J. Resp. Cell Mol. 40:575-587 (PMID: 18988921). (2009)
- Venet, F., Chung, C.S., Huang, X., Lomas-Neira, J., Chen, Y., Ayala, A. 2009. Indirect lung injury: a role for regulatory T lymphocytes in the development of pulmonary inflammation. J. Immunology 183:3472-80 (PMID: 19641139). (2009)
- Wesche-Soldato, D.E., Lomas-Neira, J., Perl. M., Chung, C.S., Ayala, A. 2008. Hydrodynamic delivery of siRNA in a mouse model of sepsis. Methods Mol. Biol. 442:67-73 (PMID: 18369778). (2008)
- Lomas-Neira, J., Chung, C.S., Ayala, A. 2008. RNA interference as a potential therapeutic treatment for inflammation associated lung injury. Inter. J. Clin. Exp. Med. 1:154-160 (REVIEW; PMID: 19079669). (2008)
- Venet, F., Chung, C.S., Monneret, G., Huang, X., Horner, B., Garber, M.E., Ayala, A. 2008. T-regulatory cell populations in trauma and sepsis. J. Leukocyte Biol. 83:523-535 (REVIEW; PMID: 17913974). (2008)
- Perl, M., Lomas-Neira, J., Chung, C.S., Ayala, A. 2008. Epithelial apoptosis and neutrophil recruitment in acute lung injury - A unifying hypothesis? What we have learned from small interfering RNAs. Mol. Med. 14:465-475 (REVIEW; PMID: 18368145). (2008)
- Venet, F., Tissot, S., Debard, A-L., Faudot, Crampe, A., Pachot, A., Ayala, A., Monneret, G. 2007. Decreased monocyte human leukocyte antigen-DR expression after severe burn injury: correlation with severity and secondary septic shock. Crit. Care. Med. 35:1910-1917 (PMID: 17568330). (2007)
- Scumpia, P.O., Delano, M.J., Kelly-Scumpia, K.M., Weinstein, J.S., Wynn, J.L., Xia, C., Winfield, R.D., Chung, C.S., Ayala, A., Heyworth, P.G., Reeves, W.H., Clare-Salzler, M.J., Moldawer, L.L. 2007. Treatment with GITR agonistic antibody corrects adaptive immune dysfunction and improves survival in murine sepsis. Blood 110:3673-3681 (PMID: 17690255). (2007)
- Delano, M.J., Scumpia, P.O., Weinstein, J.S., Coco, D., Nagaraj, S., Kelly, K.M., O'Malley, K.M, Wynn, J., Antonenko, S., Al-Quran, S., Swan, R., Chung,C.S., Atkinson, M.A., Ramphal, R., Gabrilovich, D.I., Reeves, W.H., Ayala, A., Phillips, J., LaFace, D., Heyworth, P.G., Clare-Salzler, M., Moldawer, L.L. (2007) MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T-cell suppression and TH2 polarization in polymicrobial sepsis. J. Exp. Med. 204: 1463 1474 (PMID: 17548519). (2007)
- Perl, M., Chung, C.S., Perl, U., Lomas-Neira, J.L., De Paepe, M., Cioffi, W.G., Ayala, A. 2007. Fas induced pulmonary apoptosis and inflammation during indirect acute lung injury. Amer. J. Resp. & Crit. Care. Med. 176:591-601 (PMID: 17600273). (2007)
- Wesche-Soldato, D.E., Chung, C.S., Gregory S. H., Salazar-Mathers, T.P., Ayala, C.A., Ayala, A. 2007. CD8+ T cells promote inflammation and apoptosis in the liver after sepsis: role of Fas-FasL. Amer. J. Pathol. 171:87-96 (PMID: 17478568). (2007)
- Swan, R., Chung, C.S., Albina, J.E., Cioffi, W.G., Perl, M., Ayala, A. 2007. Polymicrobial sepsis enhances apoptotic immune cell clearance by splenic macrophages. Surgery 142:253-261 (PMID: 17689693). (2007)
- Chung, C.S., Chen, Y.P., Grutkoski, P.S., Doughty, L.A., Ayala, A. 2007. SOCS-1 is a central mediator of steroid-increased thymocyte apoptosis and decreased survival following sepsis. Apoptosis 12:1143-1153 (PMID: 17380787). (2007)
- Huang, X., Venet, F., Lomas-Neira, J.L., Chung, C.S., Ayala, A. 2007. Changes in dendritic cell function in the immune response to sepsis. Expert Opin. Biol. Ther. 7:929-938 (REVIEW; PMID: 17665984). (2007)
- Lomas-Neira, J., Chung, C.S., Perl, M., Gregory, S., Biffl, W., Ayala, A. 2006. Role of alveolar macrophage & migrating neutrophils in hemorrhage induced priming for ALI subsequent to septic challenge. Amer. J. Physiol. 290:51-58 (PMID: 16157517). (2006)
- Chung, C.S., Watkins, L., Song, G.Y., Lomas-Neira, J., Cahoone, E.V., Cioffi, W.G., Ayala, A. 2006. Deficiency in gamma-delta T-lymphocytes compromises the ability of mice to survive polymicrobial sepsis. Amer. J. Physiol. 291:R1338-1343 (PMID:16878028). (2006)
- Wesche, D.E., Lomas-Neira, J.L., Perl, M., Chung, C.S., Ayala, A. 2005. Leukocyte apoptosis and its significance in sepsis and shock. J. Leukocyte Biol. 78:325-337 (REVIEW; PMID: 15817707). (2005)
- Perl, M., Chung, C.S., Ayala, A. 2005. Apoptosis. Crit. Care Med.-Supplt. 33:S526-S529 (REVIEW; PMID: 16340441). (2005)
- Lomas-Neira, J.L., Perl, M., Chung, C.S., Ayala, A. 2005. Shock and hemorrhage: An overview of animal models. Shock 24 (Suplt. 1): 33-39 (REVIEW; PMID: 16374370). (2005)
- Perl, M., Chung, C.S., Lomas-Neira, J., Rachel, T.M., Biffl, W.L., Cioffi, W.G., Ayala, A. 2005. Silencing of Fas- but not caspase-8 in lung epithelial cells ameliorates experimental acute lung injury. Amer. J. Pathol. 167:1545-559 (PMID: 16314469). (2005)
- Wesche-Soldato, D.E., Chung, C.S., Lomas-Neira, J., Doughty, L.A., Gregory S. H., Ayala, A. 2005. In vivo delivery of caspase 8 or FAS siRNA impoves the survival of septic mice. Blood. 106:2295-2301 (PMID: 15941915). (2005)
- Song, G.Y., Chung, C.S., Cioffi, W.G., Ayala, A. 2005. Insights into the contribution of STAT4 and STAT6 signaling to the morbidity seen in a low-mortality model of sepsis. Intensive Care Med. 31:1564-1569 (PMID: 16172848). (2005)
- Lomas-Neira, J.L., Chung, C.S., Wesche, D.E., Perl, M., Ayala, A. 2005. In vivo gene silencing (with siRNA) of pulmonary expression of MIP-2 vs. KC results in divergent effects on hemorrhage induced neutrophil mediated septic acute lung injury. J. Leukocyte Biol. 77:846-853 (PMID: 15695553). (2005)
- Ding, Y., Chung, C.S., Bray, S., Chen, Y., Grutkoski, P.S., Carlton, S., Albina, J.E., Ayala, A. 2004. Polymicrobial sepsis induces divergent effects on splenic and peritoneal dendritic cell function in mice. Shock 22:137-144 (PMID: 15257086). (2004)
- Lomas-Neira, J.L., Chung, C.S., Grutkoski, P.S., Miller, E.J., Ayala, A. 2004. CXCR2 inhibition suppresses hemorrhage induced priming for acute lung injury in mice. J. Leukocyte Biol. 76:58-64 (PMID: 15123771). (2004)
- Grutkoski, P.S., Chen, Y., Chung, C.S., Cioffi, W.G., Ayala, A. 2004. Putative mechanism of hemorrhage-induced leukocyte hyporesponsiveness: induction of suppressor of cytokine signaling (SOCS)-3. J. Trauma 56:742-748 (PMID: 15187736). (2004)
- Grutkoski, P.S., Chen, Y., Chung, C.S., Ayala, A. 2003. Sepsis-induced SOCS-3 expression is immunologically restricted to phagocytes. J. Leukocyte Biol. 74:916-922 (PMID: 12960286). (2003)
- Rhee, R.J., Carlton, S., Lomas, J.L., Lane, C., Brossay, L., Ayala, A. 2003. Inhibition of CD1d activation suppresses septic mortality: a role for NK-T cells in septic immune dysfunction. J. Surg. Res. 115:74-81 (PMID: 14572776). (2003)
- Lomas, J.L.,Chung, C.S., Grutkoski, P.S., LeBlanc, B.W., Lavigne, L., Reichner, J., Gregory, S.H., Doughty, L.A., Cioffi, W.G., Ayala, A. 2003. Differential effects of MIP-2 and KC on hemorrhage induced neutrophil priming for lung inflammation: assessment by adoptive cell transfer in mice. Shock 19:358-365 (PMID: 12688548). (2003)
- Chung, C.S., Song, G.Y., Lomas, J., Simms, H.H., Chaudry, I.H., Ayala, A. 2003. Inhibition of Fas/Fas ligand (FasL) signaling during sepsis has tissue specific effects on macrophage apoptotic and functional capacity. J. Leukocyte Biol. 74:344-351 (PMID: 12949237) (2003)
- Ayala, A., Chung, C.S., Lomas, J.L., Song, G.Y., Doughty, L.A., Gregory, S.H., Cioffi,W.G., LeBlanc, B.W., Reichner, J., Simms, H.H., Grutkoski, P.S. 2002. Shock induced neutrophil mediated priming for acute lung injury in mice: divergent effects of TLR-4 and TLR-4/FasL deficiency. Amer. J. Pathology 161:2283-2294 (PMID: 12466142). (2002)
- Song, G.Y., Chung, C.S., Chaudry, I.H., Ayala, A. 2001. MAPK p38 antagonism as a novel method for inhibiting lymphoid immune suppression in polymicrobial sepsis. Amer. J. Physiol. 281:C662-C669 (PMID: 11443065). (2001)
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