Inflammation 1

inflammation

protective response of the host aimed at:

• eliminating the initial cause of cell injury

• clearing necrotic cells & debris

• initiating tissue repair

typical acute inflammatory response

• recognition of the offending agent by resident cells

• release of mediators (recruit leukocytes)

• vasodilation & increase vascular permeability (edema)

• activation of leukocytes to destroy & eliminate the offending agent

• release of cytokines to resolve or repair by ECM deposit by fibroblasts

resident innate immune cells

• macrophages & dendritic cells

• detect pathogens/ damage-associated signals & rapidly initiate the inflammatory response

• express receptors w/ limited specificity, but respond immediately, enabling rapid detection of infection/ injury

PAMPs

• pathogen associated molecular patterns

• molecules common to many pathogens

• recognized by cells of the innate immunity through PRRs (TLRs & NLRs)

DAMPs

• damage associated molecular patterns

• endogenous molecules shed by damaged or dying cells due to trauma/ an infection by a pathogen

• also recognized by PRRs

PRRs

• pattern recognition receptors

• cells of the innate immunity

  • Toll like receptors (TLR)

  • nucleotide-binding oligomerization domain like receptors (NLRs)

binding of TLRs to PAMPs/DAMPs →

activation of transcription factors like NF-kB which translocated to the nucleus to induce the transcription of pro-inflammatory cytokine genes (IL-1B & IL18)

NF-Kb

often called the “molecular switch of inflammatory response”

NLRP3

• NOD

• LRR

• Pyrin domain-containing protein 3

• member of the NLR family that acts as an intracellular sensor for PAMPs, DAMPs, & metabolic crystals

Fully assembly of NLRP-3 inflammasome causes auto-catalytic cleavage of pro-caspase 1→

active caspase 1 → pro-interleukin-1B → active form (IL-1B) → acute inflammation

dilation of arterioles mainly caused by

relaxation of vascular smooth muscle cells by different cell mediators: histamine, nitric oxide

increased permeability of the microvasculature

• allows the escape of plasma proteins & leukocytes from vascular system into interstitial (extravascular) spaces

• result → leakage of protein rich fluid (exudate)

edema

accumulation of fluid in interstitial (extravascular) spaces and can be inflammatory in origin or not

exudate

• inflammatory

• increase interendothelial spaces causes increase vascular permeability (cloudy)

• protein-rich fluid

• d/t inflammation

transudate

• non-inflammatory

• vessels w/ normal permeability

• protein-poor fluid (transparent)

• d/t increased vascular hydrostatic pressure (congestive HF), decrease oncotic pressure (decrease albumin)

3 sequential steps of phagocytosis

• recognition an attachment

• engulfment

• degradation & destruction

mannose receptors

bind residues of glycoproteins & glycolipids found on microbial cell walls only

scavenger receptors

bind oxidized/ acetylated LDL particles & variety of microbes

opsonic receptors

that detect host-derived proteins bound to microbes or cells (opsonins) which make them more susceptible to phagocytosis

major opsonins

• Fc fragment of IgG antibodies

• C3b breakdown product of complement

recognition & attachment

leukocytes identify & bind to microbes or tissue debris via specific receptors

engulfment

leukocyte membrane expands to surround & internalize the particle

phagosomes

pseudopods extend from leukocytes

degradation & destruction

ingested material is broken down w/in the cell using different mechanisms

histamine is released from

mast cells (performed granules)

histamine casues

dilation of arterioles & increased permeability in postcapillary venules (primary cause of increased permeability in the 1st hr after injury)

major pro-inflammatory cytokines

tumor necrosis factor (TNF) & interleukin -1 (IL-1)

nitric oxide (NO)

short-lived soluble gas synthesized from arginine by nitric oxide synthase (NOS) in the presence of O2

nitric oxide in host defense

• NO generated by iNOS

• produced by activated macrophages

• kills intracellular microbes

NO in vascular effects

• NO generated by eNOS

• produced by endothelial cells

• vascular smooth muscle relaxation

• vasodilation

bradykinin effects

• vasodilation

• increase vascular permeability (edema)

• pain***

bradykinin is made by

kallikrein enzyme cleaving high molecular weight kininogen (HMWK)

serous inflammation

• characterized by exudation of fluid poor in leukocytes in injured surface epithelial/ into body cavities

• ex. skin blisters, pleural effusion

central serous chorioretinopathy (CSC)

condition where fluid accumulates under the retina, leading to a serous retinal detachment & vision loss

fibrinous inflammation

due to more severe injuries resulting in greater vascular permeability that allows large molecules (fibrinogen) to leak & deposit on surfaces

suppurative inflammation

characterized by the collection of large amounts of purulent exudate consisting of neutrophils, necrotic cells, & edema (hordeolum & dacryocystitis)

hordeolum (stye)

acute inflammation of the eyelid glands caused by bacterial infection (typically staph aureus)

dacryocystitis

inflammation of the lacrimal sac due to bacterial infection

ulcerative inflammaion

local defects or excavations of the surface of an organ or tissue resulting from sloughing of inflammatory necrotic material

corneal ulveration

most common initial presentation of herpes simplex keratitis (inflammation caused by infection w/ HSV)

dendritic lesions

<1mm - several mm long are characteristic of herpes simplex keratitis

4 main outcomes of acute inflammation

• resolution

• suppuration

• repair & organization

• chronic inflammation