Acute tissue injury and infection Flashcards
What are the outcomes of acute inflammation?
Resolution
Organisation (to scar, adhesion)
Dissemination (sepsis, shock, death)
Chronic inflammation (replaces, insidious, accompanies)
What are the stages of resolution?
(Elimination of cause essential) Danger signals wane Anti-inflammatory signals predominate Removal of exudate and debris Recovery of tissue architecture
How do danger signals wane?
Extravasation diminishes
Neutrophil apoptosis increases
Pro-inflammatory mediators are catabolised
How do anti-inflammatory signals predominate?
- Neutrophil apoptosis is a turning point= macrophage phagocytosis of apoptotic neutrophils (efferocytosis) triggers anti-inflammatory cytokine synthesis (IL-10, TGF beta)
- anti-inflammatory mediators
- neuroendocrine inhibitors= stress hormones (cortisol, catecholamines, vagus nerve effects- sympathetic inhibitors), anti-inflammatory cytokines attenuate sickness behaviours
Name anti-inflammatory mediators
Lipid resolvins and protectins
complement inhibitors
Receptor antagonists and decoy receptor fragments
Shed annexin A1 from apoptotic neutrophils inhibits further extravasation
Acute phase proteins
How is exudate and debris removed?
- Immunoresolvant lipid mediators= supress extravasation and cytokine release, stimulate macrophage clearance and efflux to lymph/ not circulatory system
- Macrophages clear debris= emigrate in lymph or die and themselves cleared/ default state is anti-inflammatory
- Vascular permeability normalises= excess interstitial fluid deported in lymph
How is the tissue architecture recovered?
Has to have ability to regenerate and damage sufficiently limited and short-lived
(lobar pneumonia)
What happens after resolution?
Trained immunity- epigenetic changes alter how some tissues and macrophages respond again to injury (weeks/ months)
How are scars formed?
Inflamed tissue and exudate replaced with granulation tissue which remains to form collagen scar rather than regenerative tissue repair
Extensive necrosis, leftover fibrin, poor regenerative capacity
What are the problems associated with sticky fibrin adhesions?
Bind surfaces together
Fibrinous exudate binds two serosal surfaces (bowels)- intestinal obstruction
Adhesion over a whole serosal surface (symphysis)- pericardium
When is sticky fibrin adhesions protective?
Omentum designed to wrap around inflamed intestine, protecting from rupture
What is sepsis?
Excessive disseminated inflammatory reaction to infection- 20% mortality, cytokine storm of host driven state
Hyperactivated inflammation but with suppression of the adaptive immune response
Depletes inflammatory resources so secondary infection kills you
What are the clinical grades of severity for sepsis?
Sepsis- life-threatening organ dysfunction caused by the dysregulated host response to infection
Septic shock- sepsis with high serum lactate (lactic acid necrosis due to anaerobic respiration of glycolysis) and refractory low blood pressure requiring vasopressors after fluid resuscitation
Why is inflammation dangerous?
Collateral damage, danger signalling imperfect
Hazard gradient- infection hazardous in sterile vital tissues/ blood compared to friendly microbes on epithelial surfaces (different level of response- heart more so than liver)
What are the checkpoints of inflammation?
- Extent of cell injury and resident macrophage density (cloaking)
- Soluble vs particle (multiple PAMP, phagocytic processing)
- Viability (bacterial/ viral nucleic acid)
- Virulence (system surveillance)
How does hazard gradient vary?
Peripheral tissues difficult to excite immune response
Epithelial low risk, systematic circulation high risk
How are plasma protease systems mutually activating?
Co linked so if dysregulated, all dysregulated
Kinin cascade, clotting cascade, complement cascade, fibrinolytic system
What is immunothrombosis?
Micro- thrombus traps for intravascular infection
Describe the process of immunothrombosis
- PAMP recognised by platelets, monocytes and neutrophils
- Monocytes deliver tissue factor (coagulant), fibrin coats bacteria
- Complement C3a and C5a activate platelets (triggers coagulation, Netosis and coast microbes)
- Platelets migrate, scavenge and bundle up bacteria for neutrophils
- Neutrophils activate and undergo NETosis
How are NETs involved in immunothrombosis?
NET are pro-coagulant (elastase: activate X11 and platelets)- extracellular DNA also thrombogenic
NET trap intravascular microbes- prevents dissemination
Damages nearby tissue and may escalate
What is the risk associated with immunothrombosis?
Unrestricted disseminated intravascular coagulation and inflammatory cytokine storm (sepsis)
Multiple sites of coagulation- deplete resources so further bleeding cannot coagulate properly= capillary haemorrhage in soft tissues
Micro-thrombi of bacteria can block vessel lumen if dysregulated
Name a microbial counter-strategy to immunothrombosis
Streptococcus- streptokinase and DNAse degrade fibrin and NET
What are clinical settings of sepsis?
Pneumonia, UTI, abdominal infection
Negative infection screening 1/3
Pro-inflammatory tissue damage and susceptibility to second infection
How do tissue injuries/ ischemia vary in sepsis?
Pathogen factors- virulence, load, PAMPS
Host factors- genetics, therapy, comorbidity
How do tissue injuries in sepsis occur?
Viscous cycles of tissue hypo-oxygenation and necrosis
Dysregulation of; innate immunity (phagocytes, platelets, complements), supressed adaptive immunity, coagulation (tissue factor, PAR1)
How does UTIs often lead to sepsis?
Urine incontinence and confusion in elderly patients leads to urinary catheter- decoy foreign body, irritant (sterile inflammation/ cystitis), microbial niche (biofilm), local phagocytic defect/ immunosuppression, privilege site for bacterial proliferation- direct route to grow up
How can phagocytosis be undermined?
Slippery/ slime capsule- pneumococcus vs decoy foreign body (suture)
Frustrated by slime
Intracellular organisms evade (tuberculosis)
How may (elderly) patients test positive for kidney inflammation?
Renal function decline/ signs of sepsis
Urine bacterial culture positive/ neutrophil casts in urine
Leukocyte cast in shape of kidney tubule
What is the diagnosis of pus in kidney tubule?
Ascending UTI
Complicated by acute pyelonephritis, sepsis
Risk of worsening to multiorgan failure despite treatment
