University at Buffalo
The Witebsky Center

The Witebsky Center
University at Buffalo
Bacteriology hostmicrobe immunology parasitology virology bioinformatics mycology
The Witebsky Center The Witebsky Center
Paul R. Knight., Ph.D.
Paul R. Knight, M.D., Ph.D.
Professor
Departments of Anesthesiology and Microbiology
Phone: (716) 829-3582
Fax: (716) 829 2172
Email: pknight@buffalo.edu
pKnight

1)     Pathogenesis of Aspiration Pneumonitis (PI-Dr. Paul Knight, funded NIH grant #HL48889) – Our laboratory has developed a rat model of gastric aspiration pneumonitis, a major risk factor for developmejnt of Acute Respiratory Distress Syndrome (ARDS).  An extremely complex project involving lung injury-induced inflammatory mechanisms that are currently not well understood.  This project will (and has) produced results of considerable clinical importance regarding this potentially serious complication of anesthesia.  Areas currently under investigation are:  a) exacerbation of gastric aspiration inflammatory injury by hyperoxia (e.g. the role of superoxides and othyer mediators of oxidative injury), b) elucidation of the pathogenesis of lung injury (e.g. inflammatory mediators release) resulting from acid exposure, particular exposure, and by their combination, c) the role of proinflammatory cytokines and chemotractants in the inflammatory process, d) various treatment regimens, such as:  anti-oxidants, various cytokine and chemokine antibodies, as well as specific adenovirus construct administration to induce cytokine overexpression.  Specific techniques involved in this project are:  small animal surgery (rat and mouse), lung function assessment (gas exchange, shunting, compliance), lung injury assessment (albumin permeability, wet-dry weight), enzyme kinetic assays, ELISAs, cytotoxicity assays, HPLC amino acid analysis, surfactant-producing type II cell ixolation, as well as alveolar macrophage isolation, and subsequent function measurement, flow cytometric characterization of inflammatory cell infiltration and intracellular cytokine production, and Rnase Protection assay analysis of mRNA.  “Knock-out” mice technology is also being utilized to pinpoint involvement of specific gene products during the course of the injury.  Furthermore, in collaboration with Dr. Thomas Russo (Department of Medicine-Infectious Disease Division) from the Witebsky Center for Microbial Pathogenesis and Immunology (of which, Dr. Knight is also a member), we are investigating the role that gastric aspiration may play in the patient’s susceptibility to Gram-negative pneumonia and subsequent degeneration to ARDS using many of the techniques and approaches described above.  

2)     Host Response to Post-Operative Pneumonia (PI-Dr. Paul Knight, pending NIH grant #AI/HL46534) – Post-operative pneumonia continues to be a dangerous risk to patients and its underlying pathogenesis is still poorly understood.  Modulation of the immune/inflammatory system by surgical stress and/or viral respiratory tract infections may be a contributing factor to that risk.  The goals of this project are to determine the effects of anesthesia/surgery during different periods of viral respiratory tract infections on host antibacterial defenses using an influenza-infected mouse model developed in this laboratory.  Interrelationships between pro- and anti-inflammatory cytokine networks are examined to develop potential treatments to either prevent or intervene in post-operative Gram-negative pneumonia scenarios.  The specific techniques described above for Project #1 are also utilized in this project. 

3)     Pulmonary Inflammatory response in COPD Surgery Patients (PI-Dr. Paul Knight, pending NIH grant #HL66544) – The goals of this project are to determine the effects of anesthesia/surgery on host antibacterial defenses and lung function in Chronic Obstructive Pulmonary Disease (COPD) patients.  Interrelationships between pro- and anti-inflammatory cytokine networks, as well as alveolar macrophage phenotype will be examined to develop potential treatments to either prevent or intervene in post-operative complications often associated with these patients.  This condition presents many of the characteristics of the animal lung injury models in a human clinical setting.  Utilizing the techniques and expertise from the projects described above, it is hoped that findings in the animal models may be extrapolated to this clinical setting. 

4)    Bacterial Modulation of Lung Inflammatory Response (PI-Dr. Thomas Russo, pending NIH grant #AI/HL44843) – This project is being carried out in a collaborative effort with Dr. Thomas Russo’s laboratory.  The goals of this project are to determine the mechanisms by which the bacterial capsule and O-specific antigen modulate neutrophil recruitment into the lungs in a diametrical manner and extend our evaluations on the relative roles of bacterial factors (e.g. hemolysin) and bacterially-induced host response elements in directly mediating the pathogenesis of lung injury.  The specific techniques described above for Project #1 are also utilized in this project, as well as the use of genetically-altered mutants of an extraintestinal pathogenic strain of E. coli developed and produced in Dr. Russo’s laboratory.  

5)    Brain-derived Tumor Necrosis Factor (TNF) and Adrenergic Responses in Neuropathic Pain (PI-Dr. Robert Spengler, pending NIH grant #NS/GM41352) – This project is being carried out in a collaborative effort with Dr. Robert Spengler’s (Department of Pathology) laboratory.  The goal of this project is to examine the role of cytokine-induced adrenergic neuroplastic changes in the central nervous sytem (CNS) to the pathogenesis of hyperalgesia.  Early experiments demonstrate that in the Bennett model of neuropathic pain, expression of TNFa increases in nuclei of the CNS associated with adrenergic nerve cell bodies.  These changes are associated with alterations in the a2-adrenergic auto-feedback response.  Local administration of anti-TNFa antibody inhibits both the development of hyperaldesia and adrenergic plasticity.  Development of effective treatment regimes for this often-time crippling condition of persistent pain is the ultimate goal of this project.  

Recent Publications:

Knight PR, Tait AR:  Operating Room Theatre Transmission of Infection.  In Wylie and Churchill-Davidson’s A Practice of Anesthesia 7th Edition.  Edited by TEJ Healy and PR Knight.  Hodder & Stoughton Ltd. Sevenoaks, UL  (In Press).

Shanley T., Davidson, BA, Nader, ND, Bless N., Vasti N., Ward PA., Johnson, KJ., Knight PR., et al:  Role of Macrophage Inflammatory Protein-2 in Aspiration-induced Lung Injury.  Crit Care Med 28:2437-2444, 2000.

Nader, ND, Ignatowski. TA, Kurek, CJ, Knight, PR, Spengler, RN.  Clonidine Suppresses Plasma and Cerebrospinal Fluid Concentrations of TNFa during the Perioperative Period.  Anesth Analg. 93:363-369, 2001.

Knight, PR, Bacon DR: An Unexplained Death:  Hannah Greener and Chloroform.  In Press Anesthesiology, 2002.

Patel, AB, Sokolowski, JJ, Davidson, BA, Knight, PR, Holm, BA:  Halothane Potentiation of Hydrogen Peroxide-induced Inhibition of Surfactant Synthesis:  The Role of Type II cell Energy Status.  Anesth Analg 94:943-947, 2002.

Covey WC, Ignatowski TA, Knight PR, Nader ND, Spenger RN:  Expression of neuron-associated TNFa in the brain is increased during persistent pain.  Regional Anes. 27:357-366, 2002.

Russo TA, Bartholomew JA, Davidson BA, Helinska JD, Carlino CB, Knight PR, Beers MF, Atochina EN, Notter, RH and Holm: Total Extracellular Surfactant is Increased but Abnormal in a rat Model of gram-negative Bacterial Pneumonia.  In press. Am. J. Physiology-lung.

Fernandez SF, Ming M-H, Davidson BA, Knight PR, Izzo JL: Cytosolic Calcium-dependency of Sympathetic Neuronal Responses to Angiotensin II:  The Calcium Switch.  Accepted pending revision.

Russo TA, Davidson BA, Prior R, Carlino CB, Helinska JD, Knight PR:  The roles of capsule and O-specific antigen from an extaintestinal  isolate in the pathogenesis of E. coli in gram-negative pneumonitis.  Submitted.  Am. Journal of Physiology.

Russo TA. Wang Z. Davidson BA. Genagon SA. Beanan JM. Olson R. Holm BA. Knight PR 3rd. Chess PR. Notter RH. Surfactant dysfunction and lung injury due to the E. coli virulence fctor hemolysin in a rat pneumonia model. American Journal of Physiology - Lung Cellular & Molecular Physiology. 292(3):L632-43, 2007 Mar.

Segal TA. Wang Z. Davidson BA.Hutson AD. Russo TA. Holm BA. Mullan B. Habitzruther M. Holland SM. Knight PR 3rd. Acid aspiration-induced lung inflammation and injury are exacerbated in NADPH oxidase-deficient mice. American Journal of Physiology - Lung Cellular & Molecular Physiology. 292(3):L760-8, 2007 Mar.

Spengler RN. Sud R. Knight PR. Ignatowski TA. Antinociception mediated by alpha (2)-adrenergic activiation involves increasing tumor necrosis factor alpha (TNFalpha) expression and restoring TNFalpha and alpha(2)-adrenergic inhibition of norepinephrine release.Neuropharmacology. 52(2):576-89, 2007 Feb.

Not Peer Reviewed:

Knight PR, Curtis L. Mendelson, M.D.: His Role in the Development of the Specialty of Anesthesiology, ASA Newsletter 63:14-16, (Sept) 1999.

Knight PR:  Developing Investigators in Anesthesiology.  ASA Newsletter 64:36, (March) 2000.

Knight PR and Holm BA:  The three components of hyperoxia (Editorial).  Anesthesiology, 93:3-5, 2000.

Chapters in Books:

Tait AR, Knight PR: Upper Respiratory Infection.  In Decision Making in Anesthesiology, 3rd Edition. Edited by LL Bready, RM Mullins, SH Noorily, RB Smith.  Mosby, Inc. St. Louis, Missouri pgs 96-97, 2000.

Bui D, Knight PR:  IgA Deficiency; Knight PR:  Immune Suppression; Knight PR, Russo TA: Rickettsial Disease/Q Fever; Knight PR, Russo TA: Rocky Mountain Spotted Fever.  In Essence of Anesthesia Practice  2nd Edition, Edited by M.F. Roizen and L.A. Fleisher, W.B. Saunders Company, Philadelphia, Pennslyvania. Pgs 192, 193, 280, 289.  2002.

Knight PR, Tait AR:  Operating Room Theatre Transmission of Infection.  In Sylie and Churchill-Davidson's A Practice of Anesthesia 7th Edition.  Edited by TEJ Healy and PR Knight.  Hodder & Stoughton LTD., Sevenoaks, UK. (In Press).

Abstracts, Preliminary Communications, Panel Discussions:

Nader ND, Li CM, Khadra WZ, Panos AL, Knight PR:  Sevoflurane-vaporized cardioplegia improves myocardial wall motion after coronary revascularization.  Anesthesiology 93:A101, 2002.

Nader ND, Li CM, Khadra WZ, Panos AL, Knight PR:  Sevoflurane-vaporized cardioplegia decreases neutrophil activation following cardiopulmonary bypass.  Anesthesiology 93A169, 2000.

Plata ET, Helinski JD, Davidson BA, Soloway P, Knight PR:  The protective role of TIMP-1 in an acid aspiration ouse model.  Anesthesiology 93:A1333, 2000.

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