Andrew Lechner, Ph.D.
Pharmacological and Physiological Science
Ph.D., University of California, Riverside, 1977
University of Colorado School of Medicine, Denver
Opportunistic infections increasingly cause septic shock and multiple organ dysfunction syndrome (MODS) in the critically ill with immunosuppression-related disease. In this setting the lungs and liver are foci of hematogenous and airborne infections that cause organ injury and pulmonary edema resulting in the acute respiratory distress syndrome (ARDS). We study the role of tissue-based and circulating leukocytes in modulating lung injury and tissue O2 delivery by using intact animals, perfused organs, and cell culture to determine the molecular regulation of proinflammatory gene expression. This approach identifies mechanisms whereby macrophage phagocytosis and secretion of cytokines including tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), and IL-6 affect the progression of ARDS and MODS.
We have shown that pathogenic fungi such as Candida albicans and bacteria (E. coli, S. aureus) induce taxonomically distinct mediator networks despite causing similar physiological changes leading to sepsis-related MODS. In striking contrast to cytokine-dependent cardiopulmonary failure in Gram-negative bacteremia or endotoxemia, candidemic shock evolves irrespective of circulating or cell-associated TNF-a and IL-1, is unresponsive to blockade of eicosanoid metabolism, and depends upon microbial viability. ARDS and lethal shock from bacteria but not fungi are blocked by antibodies against these pivotal cytokines, or are attenuated by downregulating their transcription. We have also begun to define the complex, organ-specific interactions between ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) on microbially-initiated cytokine induction. Sequential I/R and H/R occur frequently during trauma and infection, and can influence the integrity of critical pro-inflammatory host defense mechanisms via changes in cellular oxidation/reduction status. We utilize a full range of molecular biological approaches to further our understanding of which surface receptors and cytoplasmic factors ultimately regulate the translational efficiency of cytokine gene expression.
In addition to leukopenia we have attempted to reverse acquired immune deficiencies and transplant-related defects due to glucocorticoid therapy using immunoadjuvants including bacterial tripeptides and recombinant colony-stimulating factors. These studies address critical questions regarding the use of biological response modifiers to prime residual antimicrobial host defenses during immunosuppression. We have shown that such mechanistic therapies abrogate sepsis-related ARDS and MODS, thereby enhancing survival in this growing patient population.
Lechner, A.J., G. M. Matuschak, and D. S. Brink. (2012) Human Organ Systems: Respiratory – An Integrated Approach to Disease, New York: McGraw-Hill; 424 pp. (advance copies available October 1, 2011). Primary audience: second-year M.D. students who attend medical schools with an “organ systems” approach in their curricula (estimated by the AAMC to be at least 40% nationwide).
Representative Recent Peer-Reviewed Papers
- Knuepfer, M. M., T. A. Bloodgood, G. M. Matuschak, and A. J. Lechner (2004) Cocaine enhances susceptibility to endotoxemic shock in a subset of rats. Crit. Care Med. 32:175-183.
- Matuschak, G. M., A. J. Lechner, Z. Chen, S. Todi, T. M. Doyle, and L.L. Loftis (2004) Hypoxic suppression of E. coli-induced NF-kB and AP-1 transactivation by oxyradical signaling. Am. J. Physiol. 287:R437-R445.
- Mukhopadhyay, S., S. Das, E. A. Williams, D. Moore, J. D. Jones, D. S. Zahm, M. M. Ndengele, A. C. Howlett, and A. J. Lechner (2006) Lipopolysaccharide and cyclic AMP regulation of CB2 cannabinoid receptor levels in rat brain microglia and mouse RAW 264.7 macrophages. J. Neuroimmunol. 181:82-92.
- Matuschak, G. M., and A. J. Lechner (2010) Acute lung injury and the acute respiratory distress syndrome: pathophysiology and treatment. Missouri Medicine 107:194-200.
- Doyle, T. M., G. M. Matuschak, and A. J. Lechner (2010) Septic shock and non-pulmonary organ dysfunction in pneumonic plague: the role of Yersinia pestis pCD1- vs. pgm- virulence factors. Crit. Care Med. 38:1574-1583.
- Matuschak, G. M., R. Nayak, T. M. Doyle, and A. J. Lechner (2010) Acute hypoxia decreases E. coli LPS-induced cytokine production and NF-kB activation in alveolar macrophages. Respir. Physiol. & Neurobiol. 172:63-71.
- Wilson, C. N., C. O. Vance, T. M. Doyle, D. S. Brink, G. M. Matuschak, and A. J. Lechner (2011) A novel post-exposure medical countermeasure L-97-1 improves survival and acute lung injury following intratracheal infection with Yersinia pestis. Infect. Immun. (17 pp., in press, due December issue).
Representative Recent Published Abstracts
- Matuschak, G. M., T. M. Doyle, Z. Chen, and A. J. Lechner (2005) Microarray analysis of early postbacteremic liver and lung gene expression following hypoxic stress. Crit. Care Med. 32:A489.
- Ndengele, M. M., T. M. Doyle, D. Salvemini, A. J. Lechner, and G. M. Matuschak (2006) Superimposed brief hypoxia modulates endotoxin-induced activation of p38 mitogen-activated protein kinase (MAPK) and AP-1 DNA binding in RAW 264.7 macrophages. Am. J. Respir. Crit. Care Med. 174:A136.
- Doyle, T. M., L. Chen, G. M. Matuschak, and A. J. Lechner (2007) Yersinia pestis Lcr virulence factors mediate intrapulmonary cytokine expression in rat primary plague pneumonia. FASEB J. 21:A551.
- Lu, L. W., S. M. Stack, T. M. Doyle, V. L. Salvato, G. M. Matuschak, and A. J. Lechner (2008) Structural and functional liver injury following primary plague pneumonia initiated by pCD1+ Yersinia pestis. Crit. Care Med. 35:A58.
- Doyle, T. M., A. Lechner III, Z. Chen, G. M. Matuschak, and A. J. Lechner (2008) Yersinia pestis pCD1 virulence factors mediate hepatic cytokine expression in rat primary plague pneumonia. Crit. Care Med. 35:A55.
- Wilson, C. N., C. Vance, T. M. Doyle, D. S. Brink, G. M. Matuschak, and A. J. Lechner (2009) Efficacy of L-97-1 as a medical countermeasure in a bioterrorism animal model of pneumonic plague. 10th Biennial meeting of the International Endotoxin & Innate Immunity Society, Edinburgh Scotland.
- Lechner, A. J. (2011) How to Injure the Lung. An 8-hour lecture series for the 5th International Course of Respiratory Physiology, Sociedad Peruana de Neumologia, Lima, Peru.
A Novel Treatment in a Bioterrorism Model of Pneumonic Plague Targets A1 Adenosine Receptors, NIAID.
A Novel Treatment for Septicemia Targets A1 Adenosine Receptors, NIAID/NHLBI.
Animal Models of Infectious Disease, NIAID (R.M. Buller, P.I.; A.J.L, Co-Investigator).
Honors and Awards
USMLE Step 1 Physiology Committee, National Board of Medical Examiners, 2002-2006.
Distinguished Teacher Award for Humanism in the Basic Sciences, SLU M.D. Class of 2008.
Golden Apple Award as Best Teacher in the Basic Sciences, SLU’s M.D. Class of 2010.
Golden Apple Award as Best Teacher in the Basic Sciences, SLU’s M.D. Class of 2011.
Professional Organizations and Associations
American Physiological Society
American and Missouri Thoracic Societies
AAMC Graduate Research, Education & Training (GREAT) Section on M.D./Ph.D. Programs
Charter Member, National Association of M.D./Ph.D. Program Directors
St. Louis Academy of Science
Society for Critical Care Medicine