SM 243: Glucocorticoids Flashcards
What is the classic cause of Inflammation?
A response to infection
What is the classic response to inflammation?
Vasodilation, increased vascular permeability, PMN transmigration into affected tissue
What are the signs of inflammation?
Increased warmth, pain, redness, and swelling that lead to disturbance of function
What hormonal axis and what class of hormones are essential in resolving the inflammatory porcess?
Hypothalmic-pituitary-adrenal axis + glucorcorticoids are needed to resolve the inflammatory process
What can excessive inflammation lead to?
Tissue destruction and disease
What can drive excessive inflammation?
Allergies, Asthma, Autoimmune disease, Sepsis
What receptor does the HPA axis use to control inflammation?
The Glucocorticoid receptor
Describe the signaling pathway along the HPA?
Multiple signals cause the Hypothalamus to secrete CRH
CRH stimulates the release of Corticotropin from the Pituitary
Corticotropin induces the synthesis and secretion of Cortisol by the Adrenal Cortex into the bloodstream
Does Cortisol exert genomic or nongenomic effects on target cells?
Both - nongenomic is faster
What nongenomic effects does Cortisol have on target cells?
Cortisol can activate anti-inflammatory proteins that inhibit inflammatory proteins over seconds to minutes
What genomic effects does Cortisol have on target cells?
After Cortisol binds to the Glucocorticoid Receptor, the two form a complex that translocates to the nucleus and initiates transcription of RNA Poly II while repressing activity of NFkB
What effect does Cortisol have on RNA Poly II and to what end result?
Cortisol + Glucocorticoid Receptor = Complex that translocates to Nucleus; Increased transcription of RNA Poly II produces antiinflammatory proteins
What effect does Cortisol have on NFkB and to what end result?
Cortisol + Glucocorticoid Receptor = Complex that translocates to Nucleus; Blocks NFkB to decrease production of inflammatory proteins
Is RNA Poly II pro or anti inflammatory?
Anti-inflammatory, hence the Coritsol + Glucocorticoid Receptor complex increases transcription
Is NFkB pro or anti inflammatory?
Pro-inflammatory, hence the Cortisol + Glucocorticoid Receptor complex blocks transcriptional activity
Describe the Arachidonic Acid cascade and it’s relationship to inflammation?
Cytosolic Phosphoplipase A2 (PLA2) converts Triglycerides into Arachidonic Acid
COX converts Arachidonic Acid into Prostaglandin percursors
5-Lipooxygenase (LOX) converts these Prostaglandin precursors into Leukotrienes = pro-inflammatory
How does Cortisol repress Leukotriene-mediated inflammation at a protein level?
The Glucocorticoid Receptor-Cortisol comples uses a cofactor, c-Src
c-Src phosphorylates Annexin 1 to inhibit PLA2 and reduce production of Arachidonic acid, a precursor for Leukotrienes
How does the Cortisol-Glucorcorticoid Receptor complex reduce inflammation at a genomic level?
The Cortisol-Glucocorticoid Receptor complex decreases expression of AP1 and NFkB, both of which are inflammatory transcription factors
What disorders result from hyperactivity of the HPA axis?
Cushing’s Syndrome, Pain, Caloric Restriction, Immunosuppression
What disorders result from hypoactivity of the HPA axis?
Adrenal insufficiency aka Addison’s Disease
What is the strongest Corticosteroid?
Betamethasone and Dexamethasone
What does the joint swelling in RA reflect and why do we use medication?
Swelling in RA reflects synovial membrane inflammation and the goal of using medications is to reduce inflammation
What medications can be used as a first line for RA?
Methotrexate + Glucocorticoid
How are Glucocorticoids used to treat RA?
Used in low doses wit Methotrexate to achieve Low Disease Activity, and then tapered off
Also can be injected in local areas for acute inflammation
