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

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.