Chair, Vision Science Program
Optometry 226A: Systemic Pharmacology
Basic pharmacology, terminology, and concepts (both pharmacodynamic and pharmacokinetic) and pharmacotheraphy of medical conditions commonly encountered in clinical optometric practice (including cardiovascular disease, respiratory disease, diabetes, infection and inflammatory conditions, as well as central nervous system disorders)
Optometry 226B: Ocular Pharmacology
Basic pharmacology, terminology, and concepts (both pharmacodynamic and pharmacokinetic) as applied to the eye and ophthalmic drugs, clinical prescribing issues including formulation, dosing and prescribing, and pharmacotherapy of anti-inflammatory, centrally acting, hormonal and other “specialist” systemic drugs.
Intrinsic Protective Circuits in Ocular Inflammatory, Immune and Wound Healing Responses
Inflammation is a highly regulated and elegant response to injury, stress and infection. At any given time in life there are multiple sites of healthy and temporary inflammation that often go unnoticed in tissue/organs such as skin, gastrointestinal tract, mouth, eyes, blood vessels and lungs. More importantly, inflammation is essential to health and survival of all living organisms. Healthy inflammation protects a wound against invading bacteria/viruses, removes dead tissue and cells and regulates the repair of injured or stressed tissue. By design a healthy inflammatory response is beneficial, temporary, resolves naturally, and restores normal function of the afflicted tissue/organ.
Unfortunately, the complex regulation of healthy inflammation is in a precarious balance that can tip towards causing unwanted tissue damage and lead to abnormal or chronic inflammation. Diet, overall state of health, and environmental factors can tip healthy inflammation to an uncontrolled and disease causing inflammatory event. Dysregulated inflammation is now recognized as a major factor in the global disease burden and the cause of cardiovascular diseases (atherosclerosis, heart attacks, stroke), asthma, arthritis, allergies, cancer and blindness. Traditionally therapeutic approaches have focused simply on inhibiting pathways that initiate or amplify inflammation, which can lead to significant and potentially dangerous side effects.
Research efforts in the Gronert Laboratory are part of a new paradigm that has established lipid circuits as critical regulators for the successful execution of a normal healthy inflammatory response. These lipid circuits are essential components of a “resolution program” that helps remodel injured tissue, removes spent white blood cells and naturally terminates the inflammatory response. Intense research efforts in the last few years by a small group of research teams around the world has spurred enormous interest in these resident protective lipid circuits as a major target for the development of much needed novel drugs for the treatment of inflammatory diseases. Our research team is focused on elucidating the role of these endogenous protective circuits in inflammation and wound healing and to define their critical regulation by dietary omega-3 PUFA (fish oils). Karsten Gronert was a member of the research team that discovered that fish oils (omega-3 PUFA) are converted to specific protective lipid signals in the body. These findings have provided a molecular mechanism for the remarkable beneficial actions of dietary omega-3 PUFA, which has eluded scientist for decades.
Research project in the laboratory employ innovative approaches and state-of-the art technology to discover and define the endogenous role of protective lipid circuits in the body and cells with the long-term goal of identify novel drug targets or treatment options for inflammatory diseases. Our main research project is sponsored by the National Eye Institute and is focused on elucidating the formation and molecular mechanisms of protective lipid signals in the sequelae of ocular injury. Our research efforts in the last few years have uncovered that protective lipid mediator circuits and “resolution programs” are highly and selectively expressed in the delicate visual axis. Current efforts are aimed at defining the role and regulation of these intrinsic protective pathways and “resolution program” in normal ocular physiology and inflammatory diseases. In addition, the Gronert laboratory collaborates with leading research teams at Children’s Hospital/Harvard Medical School, Charité University Clinic in Germany and the National Institute for Digestive and Diabetes and Kidney Disease to define the role and molecular mechanisms of action for omega-3 PUFA circuits in healthy humans and human patients with inflammatory diseases as well as in experiments that model the leading causes of blindness.
Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med, 2000.
Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nature Imm 2001
Hong, S, Gronert, K., Devchand, P.R., Moussignac, RL, and Serhan, C.N.. Novel docosatrienes and 17S-Resolvins generated from docosahexaenoic acid in murine brain, human blood and glial cells: Autacoids in anti-inflammation. J Biol Chem 2003
Gronert K, Maheshwari, N, Khan, N, Hassan, I R, Dunn, M, and Laniado Schwartzman, M. A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense.J Biol Chem, 2005
Gonzalez-Periz, A, Planaguma, A, Gronert, K, Miquel, R, Lopez-Parra, M, Titos, E.,Horrillo, R, Ferre, N, Deulofeu, R, Arroyo, V, Rodes, J, Claria, J. Docosahexaenoic acid (DHA) blunts liver injury by conversion to protective lipid mediators: Protectin D1 and 17S-hydroxy-DHA. FASEB J, 2006
Seta, F, Bellner, L, Rezzani, R, Regan, R F, Dunn, M W, Abraham, N G, 1Gronert, K and Laniado-Schwartzman, M Heme-oxygenase: A critical determinant for execution of an acute inflammatory and reparative response. Am J Path, 2006
Biteman, B, Hassan, I R, Walker, E., Leedom, A J, Dunn, M, Seta, F, Laniado-Schwartzman, M, and Gronert, K. Interdependence of lipoxin A4 and heme-oxygenase in counter-regulating inflammation during corneal wound healing. FASEB J, 2007
Mumy KL, Bien JD, Pazos MA, Gronert K, Hurley BP, McCormick BA. Distinct isoforms of phospholipase A2 mediate the ability of Salmonella enterica serotype typhimurium and Shigella flexneri to induce the transepithelial migration of neutrophils. Infect Immun. 2008; 76: 3614-3627
Qin, Q, Patil, K, Gronert, K1, Sharma, S1. Neuroprotectin D1 inhibits retinal ganglion cell death following axotomy. Prostaglandins, Leukotrienes and Essential Fatty Acids 2008; 79: 201-207 (1Corresponding Authors)
Pazos, M, Siccardi, D, Mumy, KL, Bien, JD, Louie, S, Shi, HN, Gronert, K, Mrsny, R and McCormick, BA. Multidrug resistance transporter 2 regulates mucosal inflammation by facilitating the synthesis of hepoxilin A3. J Immun 2008; 181:8044-8052
Hassan, I and Gronert, K. Acute changes in dietary ω-3 and ω-6 PUFA have a pronounced impact on survival following ischemic renal injury and formation of renoprotective docosahexaenoic acid-derived PD1. J Immun 2009; 182:3223-3232
Gonzalez-Periz, A, Horrillo, R, Ferre, N, Gronert, K, Dong, B, Moran-Salvador, E, Titos, E, Martinez Clemente, M, Lopez-Parra, M, Arroyo, V and Claria, J. Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids. A role for resolvins and protectins. FASEBJ, 2009; 23:1946-1957
Leedom, AJ, Sullivan, AB, Dong, B, Lau, D and Gronert, K. Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic injury. Am J Pathol 2010; 176:74-84
Liclican, EL, Nguyen V, Sullivan AB, and Gronert K. Selective activation of the prostaglandin E2 circuit is a key component of chronic injury-induced pathological angiogenesis. Invest Ophthalmol Vis Sci 2010; 51(12):6311-20
Hurley BP, Pirzai W, Mumy KL, Gronert K, McCormick BA. Selective eicosanoid-generating capacity of cytoplasmic phospholipase A2 in Pseudomonas aeruginosa-infected epithelial cells. Am J Physiol Lung Cell Mol Physiol 2011; 300:L286-L294
Sapieha P, Stahl A, Chen J, Seaward MR, Willett KL, Krah NM, Dennison RJ, Connor KM, Aderman CM, Liclican E, Carughi A, Perelman D, Kanaoka Y, Sangiovanni JP, Gronert K, Smith LE. The 5-lipoxygenase metabolite 4-HDHA mediates specific anti-angiogenic effects of ω-3 PUFAs in proliferative retinopathy. Science Translational Medicine 2011; 3:69ra12
Tiruvengada T, Prajna NV, Gronert K, Oldenburg KE, Ray KJ, Keenan JD, Lietman TM, Acharya NR. Gender Differences in Re-Epithelialization Time in Fungal Corneal Ulcers. Br J Ophthalmol 2011; 96(1):137-8
Wang SB, Hu KM, Seamon KJ, Mani V, Chen Y, Gronert K. Estrogen negatively regulates epithelial wound healing and protective lipid mediator circuits in the cornea. FASEB J. 2012; 26(4): 1506-16
Gronert, K. and Hassan I R. Reaping the benefits of renal protective lipid autacoids. Drug Discovery Today: Disease Mechanisms, 2007
Gronert, K. Lipid Autacoids in Inflammation and Injury Responses: A Matter of Privilege. Molecular Interventions. 2008.
Liclican, E and Gronert K. Molecular Circuits of Resolution in the Eye, The Scientific World J 2010; 10: 1029-1047
Gronert, K. Resolution, the Grail for Healthy Ocular Inflammation, Exp Eye Res, 2010, in press
Gronert, K. The protective role of omega-3 in eye disease – new insights, Expert Rev Ophthalmol 2011, in press
Gronert, K. Ocular Inflammation Models, Chapter 31, in Fundamentals of Inflammation,
Editors: Serhan, Ward and Gilroy, Cambridge University Press; 2010