| What is an inflammation? | Beneficial host response to foreign invaders and necrotic tissues, but can cause tissue damage.
Main components are vascular reaction and cellular response.
Steps are recognition of injured agent, recruitment of leukocytes, removal of agent, repair |
| What are the general causes of inflammation? | Infection, tissue necrosis, foreign bodies, trauma, immune response.
Epithelia, macrophages, DC, leukocytes recognize the microbes and necrotic tissues by their PRRs, while microbes in blood are recognized by circulating proteins.
Outcome of acute inflammation is elimination of the stimulus, repair of damaged tissue or persistent injury thus chronic inflammation. |
| What is acute inflammation? | It consists of 3 components: Dilation of small vessels, Increased permeability of microvessels, migrating leukocytes from microcirculation to the injury focus to eliminate the offending agent |
| What are the different features of chronic and acute inflammation? | Onset (fast vs slow)
Cellular infiltrate (neutrophils vs macrophages and lymphocytes)
Tissue injury (mild vs severe progressive)
Local signs (prominent vs less) |
| What is the blood vessels reaction in acute inflammation? | Changes in blood flow and permeability, to maximize movement of plasma proteins and leukocytes to site of injury.
Fluid and proteins leave the vascular system by exudation process
(exudate: rich in proteins, Transudate : poor in proteins via osmotic imbalance) |
| What is edema? | Excess fluid in interstitial tissue, can be exudate or transudate.
Pus is a purulent exudate rich in leukocytes, dead cell debris and microbes (maybe) |
| How do vessels react with inflammation? | Vasodilation induced by mediators (histamine), it is the first manifestation of inflammation (may be preceded by vasoconstriction.
Starts with arterioles and moves to capillaries leading to increased blood flow to site of inflammation (causing erythema and chalour)
It is followed by increased permeability of vessels outpouring exudate. Slower blood flow and increased viscosity occurs.
Resulting in stasis of blood flow and seen as vascular congestion with localized redness causing neutrophils to accumulate. |
| How is increased vascular permeability occurring in endothelial cells? | Retraction of endothelial cells (opening interendothelial spaces, elicited by histamine, bradykinin, leukotrienes, other chemicals.
Occurs after exposure to mediator short lived, immediate transient response.
Occurs at post-capillary venules
Endothelial injury also increases vascular permeability due to necrosis and detachment, so direct damage to endothelium is encountered in severe injuries, neutrophils adhere to injured endothelia and amplify this reaction.
Starts just with the injury and stays hours until damaged vessels are thrombosed or repaired |
| How is the leukocyte recruitment to site of inflammation? | Mostly neutrophils (rapid) and macrophages, neutrophils use enzymes to mount response while macrophages use new transciption.
Mediated by adhesion molecules and cytokines. |
| How is leukocyte adhesion to endothelia? | Laminar flow gets leukocytes to post-capillary venules wall, then when blood stasis occurs white cells position along endothelial surface (margination), then they detect endothelial change and adhesion molecules to roll through endothelia and adhere to injury point (all mediated by cytokines) |
| How is leukocyte migration through endothelia? | By squeezing in between process called transmigration (in post-capillary venules)
Driven by chemokines Igs and Platelet Endothelial Cell Adhesion Molecule (PECAM-1) mediate binding event.
They pierce the basal lamina secreting collagenase, vessel wall not injured. |
| What are adhesion molecules? | Selectins (weak interaction between leukocytes and endothelium) e.g: L, E and P selectins ( L neutrophils other endothelium)
Integrins (firm reaction) e.g: LFA, MAC, VLA, a4b7 |
| What is chemotaxis of leukocytes? | Leukocyte movement to site of injury after leaving the circulation stimulated by chemical.
Exogenous and endogenous chemotactic molecules (bacterial, cytokines, complements (C5a), Lipooxygenase pathway of AA)
Nature of leukocyte infiltrate depends on the age of inflammation and type of stimulus (starts neutrophils becomes lymphocytes and macrophages) |
| What are properties of neutrophils and macrophages? | . |
| How is phagocytosis and clearance of offending agent? | Leukocyte activation after recognition of microbes, then they destroy them by phagocytosis and intracellular killing (after becomes active)
Sequential steps of phagocytosis are Recognition, Engulfment, and Killing |
| How is the recognition by phagocytic receptors for phagocytosis? | Its effieciency increases when microbes are opsonized (by Igs, C3b and lectins which are recognized by leukocytes) |
| How is engulfment process of phagocytosis? | Pseudopods (cytoplasm extensions) flow around microbe, then enters as a phagosome, which fuses lysosome and starts degrading it.
Phagocyte may also release some granule contents to extracellular space damaging innocent cells |
| How is intracellular destruction of microbes and debris occurring? | By ROS, reactive nitrogen species (RNS), derived from NO and lysosomal enzymes.
This is the final step of elimination of microbes and necrotic cells.
Cells may also release toxins and proteases extracellularly |
| What are ROS? | Reactive oxygen species, produced by rapid assembly and activation of enzyme phagocyte oxidase (NAPH oxidase) forming superoxide (O2.)
In neutrophils it is called respiratory burst, and ROS are produced in phagolysosomes where superoxide is then transformed into H2O2.
Then myeloperoxidase enzyme converts H2O2 to OCl2- hypochlorite, which is the anti-microbial agent destroying bacteria by halogenation or oxidation. |
| Talk about NO? | NOS induces production of NO when macrophages are activated by cytokines or microbial products, NO reacts with O2. generating high reactive peroxynitirite which attack damage lipids, protein nucleic acids of microbes
NOS presents in cytoplasm and exerts NO to lysosome |
| What are granule enzymes? | Neutrophils and macrophages contain granules packed with enzymes and anti-microbial products that degrade microbes and necrotic tissues |
| What are neutrophil extracellular traps? | NETs fibrillar proteins produced by neutrophils that entrap microbes, forming a viscous meshwork of nuclear chromatin binding granule and anti-microbial proteins.
They provide a defense mechanism not involving phagocytosis. |
| How is the termination of acute inflammatory response? | After offended agents are removed inflammation declines since no more mediators (and the ones produced already have a short half-life.
Also neutrophils have short half lives and die by apoptosis.
In addition there are stop signals terminating inflammation actively |
| What are the morphological patterns of acute inflammation? | Dilation of small vessels, accumulation of leukocytes and fluid in extracellular tissue
Depending on severity of inflammation and tissue involved morphologic pattern differs, giving us an idea of the underlying cause of inflammation according to the morphology seen. |
| How are congestive and edematous inflammation? | Congestion and edema (intense vasodilation and abundant exudate)
E.G: Viral infection causing lung edema, Colds causing swelling of nasal mucosa and First degree burn/ type I hypersensitivity |
| How are hemorrhagic inflammations? | Increased capillary permeability and endothelial damage cause red cells leakage (erythrodiapedesis)
E.g: Vasculitis, Hemorrhagic pulmonary edema of influenza, acute relapse of Ulcerative colitis. |
| How are serous inflammations? | Exudation of cell-poor fluid to spaces of injury, not infected by destructive organisms and no leukocytes.
May be plasma-derived (increased permeability) or mesothelial secretion (local irritation)
AKA effusion.
E.g: skin blister from burn or viral infection |
| How are fibrinous inflammations? | Large vascular leaks or local procoagulant stimulus.
Fibrinogen passes through endothelia and fibrin clots are formed in extracellular space.
Usually of lining body cavities (meninges, pericardium and pleura)
Histology: eosinophilic threads or amorphous coagulum
They are dissolved by fibrinlysis of macrophages, if not removed leads to scarring and ingrowth of fibroblasts and may cause obliteration of pericardial space |
| How are purulent inflammation abscesses? | Production of pus exudate of microbes and neutrophils (necrotic) and edema fluid.
Most frequently after bacterial infection (staph) which are pyogenic agents
E.g; Acute appendicitis.
An abscess is a localized area of purulent inflammation, they have a central region of necrotic leukocytes, and a zone of preserved neutrophils , and outside is a vascular dilation area
When persistent place of abscess (brain) we remove it surgically and cannot get rid of it auto |
| What are ulcers? | local defect of surface of an organ produced by elimination of inflamed necrotic tissue (necrosis after inflammation)
Encountered in mucosa or skin in lower limb with ischemic necrosis due to circulatory disturbance.
May be chronic (fibroblast proliferation, scarring and accumulation of leukocytes) or acute inflammations (PMNs and vascular dilations in margin) causing ulcers |
| How is necrotizing/ gangrenous inflammation? | Presence of an area of necrosis, due to anaerobic germs or ischemia, extremely serious.
E.g: gas gangrene by superinfection of a wound by anaerobe germ appendicitis.
Gangernous cholecystitis. |
| What are the outcomes of acute inflammation? | Depends on nature and intensity of inflammation, site and tissue affected, responsiveness of the host.
Three possible outcomes:
Complete resolution (restored normal, limited/ short injury or little tissue destruction, and damaged cells can regenerate)
Healing by CT replacement (scarring or fibrosis, after great tissue destruction/ tissue can't regenerate, abundant fibrin exudate that can't be cleared, may be loss of function after pus formation)
Progression to chronic inflammation (can't be resolved, persistent injurious agent/ interference w/normal process of healing, we see angiogenesis, mononuclear infiltrates, fibrosis, more seen in viral injury, chronic infection, autoimmune) |
| What is chronic inflammation? | Response to prolonged duration (weeks/months) in which we see all inflammation, tissue injury and attempts to repair together, may follow acute inflammation or begin directly |
| What are causes of chronic inflammation? | Persistent infection (mycobacteria, viruses, fungi, parasites, evoke delayed-type hypersensitivity, or acute bacterial lung infections persistent (like lung abscesses)
Hypersensitivity diseases (autoimmune/ allergic, mixed acute and chronic inflammation due to repeated bouts of inflammation)
Prolonged exposure to toxic agents (silica causing lung silicosis) |
| What are morphological features of chronic inflammation? | Infiltrates of mononuclear cells, tissue destruction, attempts of healing (angiogenesis/fibrosis) |
| What are cells and mediators of chronic inflammation? | Macrophages (secrete cytokines and GF, destroy foreign invaders, activate lymphocytes. Monocyte entry to tissues by adhesion molecules and chemokines, half-life of monocyte is 1 day while macrophage is years, and becomes dominant in inflammation w/in 48 hours make mononuclear phagocyte system, made in bone marrow and liver in embryo/yolk sac)
Eosinophils (IgE and parasitic reactions, adhesion molecules driven, have major basic protein toxic to parasites but injures epithelia, so can contribute in tissue damage by allergies)
Mast cells (both acute and chronic inflammation, bone marrow, similar to basophils but not arise from them, roles like basophils, HS reactions, IgE bound, release mediators like histamine and PGs (allergies to food/venum), secrete plethora of cytokines promote chronic inflammation)
Neutrophils (usually acute, but can be chronic for months, induced by chemokines and mediators by macrophage and T cells, in osteomyelitis can persist for months, COPD) |
| What is granulomatous inflammation? | Chronic inflammation characterized by collection of activated macrophages, T cells, central necrosis sometimes.
Activated macrophages get abundant cytoplasm look like epithelia so become called epithelioid cells, some fuse make multinucleated cells, it is a cellular attempt to contain an offending agent difficult to eradicate, strong activation of T cells leading to macrophage activation cause injury to normal tissue |
| What are types of granulomatous inflammation? | Immune granulomas (variety of agents activating T cells, when inciting agent can't be eliminated like persistent microbe/ self Ag)
Foreign body granuloma (In response to inert foreign body absence of T cell mediated immune response, typically around material like sutures, fibers not immunogenic, we see epithelioid cells apposed to surface of the body which can be identified in center of granuloma viewed w/polarized light may appear refractile) |
| How is the morphology of granulomatous inflammation? | Epithelioid cells have pink granular cytoplasm, lymphocytes surround epithelioid cells, older granulomas have rim of fibroblasts and CT, frequently seen multinucleated giant cells (40-50 microm diameter), if certain infectious organism (Tb) see central area of necrosis (caseatous necrosis, amorphous structure, eosinophilic debris)
Granuloma of Crohn disease, sarcoidosis and foreign body are non-caseating.
Healing is accompanied w/fibrosis that may be extensive |
| How is granulomatous inflammation occurring? | Encountered certain pathological state, recognizing it is important since limited causes lead to granuloma, T cell cytokines lead to chronic macrophage activation and granuloma formation, develop in some immune-mediated inflammatory disease (sarcoid, crohn), Tb, different morphology gives different dx which is necessary to know etiology by stains/cultures.. |
| Give some examples of diseases w/granuloma inflammation. | . |
| How is tissue repair? | Critical for survival, inflammation itself is to remove dangers as start repair, two reactions (regeneration by proliferation of residual cells or maturation of stem cells but not fully restored usually, and deposition of CT to form a scar in areas not able to regenerate)
Fibrosis is extensive deposition of collagen as a consequence of chronic inflammation or ischemic necrosis (MI), if it develops in areas w/inflammatory exudate, it is called organization (e.g organizing pneumonia) |
| How is repair by cell proliferation? | By GF, depends on integrity of ECM, several type (remnant of injured tissue, vascular endothelial cells, and fibroblast proliferation)
Determined by intrinsic proliferation capacity of tissues, some are labile can regenerate always proliferating (bone marrow stem cells, surface epithelia) and others are stable (G0 stage cells not proliferating only in case of injury like parenchyme (kidney liver pancreas/ endothelia, fibroblasts and smooth muscles)
others are permenant (can't regenerate like neurons and cardiac muscle cells) |
| How is mechanism of tissue regeneration? | Epithelia of intesines/skin proliferate by residual cells GF and migrate to fill defect, in parenchymal organs can occur but limited (except liver), surgical removal of one kidney leads to hyertrophy and hyperplasia of the proximal duct cells of the other kidney, restoration of normal tissue only occurs if residual tissue is intact (like acute hepatitis) |
| How is liver regeneration? | High capacity for regeneration, growth after partial hepatectomy, two mechanisms (proliferation of hepatocytes and repopulation of progenitor cells dominant mechanism depends on nature of injury (partial hepatectomy proliferation of hepatocytes, chronic injury progenitor cells) |
| How is repair by scarring? | If regeneration not sufficient, replacement of cells by CT occurs leading to scar formation, severe injury/ chronic injury, patches not restorage of tissues)
Steps are hemostatic plug and inflammation 6 min -48 hours of injury, proliferation of cells up to 10 days (eschar form), then remodeling to produce fibrous scar 2-3 weeks and up to months/ years
Macrophages are central cellular players, clear microbes and promote inflammation, produce GF leading to cell proliferation, lead to epithelial cell proliferation, angiogenesis (endothelia) and fibroblast proliferation make scar lay down collagen (form granulation tissue which is pink, soft, granular gross appearance beneath scab of a skin wound)
So healing is two types, first intension (all regeneration) and second intension (scar and regeneration) |
| How is angiogenesis? | Critical for healing, development of collaterals, tumor increase size using other blood supply than original one.
Involves sprouting new vessels from old one.
Steps: Vasodilation by NO increased permeability by VEGF, separation of pericytes from albumin surface allowing vessel sprout, migration of endothelia to tissue injury, proliferation of endothelia just behind tip of migrating cells, remodeling into capillary tube, recruitment of periendothelial cells (smooth muscle, pericytes) to form vessel, suppression of endothelia proliferation and migration and deposition of basement membrane) |
| How is remodeling of CT? | After formation of scar, it is remodeled to increase strength and contraction, cross linking of collagen and size increase increases strength, shift of collagen from type III to type I (more resilient), may recover 70-80% normal skin in 3 months if well sutured skin wound.
Wound contraction increases by myofibroblasts and later by cross-linking of collagen fibers. With time CT degrades and scar shrinks, accomplished by matrix metalloproteinases (MMP) |
| How is the morphology of granulation tissue and scar? | Granulation (fibroblast proliferation, thin wall capillaries, loose ECM, admixed w/macrophages, invades site of injury and amount of granulation depends on injury)
Scar/fibrosis (inactive, spindle fibroblasts, dense collagen, fragments of elastin (seen by trichome stain), reticulin (collagen III) |
| What are factors that impair tissue repair? | Systemic or local, intrinsic or extrinsic
Infection (delayed healing, prolongs inflammation and increases local injury)
Diabetes (compromises repair, abnormal wound healing systematic)
Nutrition (protein malnutrition and vitamin C deficiency inhibit collagen synthesis retard healing)
Steroids (anti-inflammatory, weak scars result)
Mechanical factors (increased local pressure or torsion cause wounds pull apart (dehisce))
Poor perfusion (athersclerosis or DM or varicose vein)
Foreign bodies (steel, glass, bone)
Type of injury, location of injury |
| What are some clinical examples in abnormal wound healing? | Chronic wounds (local and systemic factors cause it)
Venous leg ulcers (elderly, chronic venous HTN, fail to heal due to poor O2 delivery to site of ulcer)
Arterial ulcers (atherosclerosis, seen w/DM)
Diabetic ulcer (lower limbs, small vessel disease causing ischemia) |
| What are clinical examples of scarring abnormalities? | Excessive scarring (formation of repair components lead to keloids and hypertrophic scars [after thermal/trauma involving dermis])
Fibrosis in parenchymal organs (abnormal collagen deposition in internal organs in chronic diseases, due to persistent stimuli like chronic infection, immune rxn, lead to loss of tissue) |
| What are specific varieties of inflammation? | TB (by mycobacteria/koch bacillus, exudative, granuloma, debridment, healing, slow evolution, repeated exudative exacerbations, most often affects lungs)
Viral (2 types, cell damage directly by virus or indirect lesions by immune response, majority benign exudate turned on by necrosis of cells by viral replication, poor in polynuclear cells, and never suppurative in absence of bacteria, lymphocyte infiltrate)
Granuloma foreign body reaction
Histo patterns in relation w/some specific causes (parasites eggs (schistosomes/ leishmania), fungi (aspergillus, pneumocystitic), bacteria (acid-fast), foreign bodies. |
| How is evolution of TB inflammation? | Exudative phase (congestion, edema, polynuclear influx, occurs only if we see large BKs number in Zeihl-Nelson stain, no suppuration but caseatous necrosis, which depends on immune status, yellow-white lesion eosinophilic anhist area)
Tuberceloid granuloma (Around caseatous necrosis or in its absence in exudative phase, polynuclear cells disappear, lymphocytes and epitheliod cells which can merge form multinucleated cell, horseshoe arrangement (langerhans cells), grouped into nodules)
Inflammation (not directly related to BK, more type IV HS, inhibit evolution to fibrosis by outbreaks of disease (new lesion) or presence of caseum in inflammatory focus) so we see lesions of different ages in chronic TB lung, can subsit for years) |
| How is caseum evolution? | The debridement of the caseum :
✔ Internal debridement by macrophages is ineffective in removing the caseum.
✔ External debridement is possible :complex process, begins with the softening of the caseum: it becomes of liquid consistency, the polynuclear flowing into it t, The BK multiply very actively.The softened caseum is then removed in different ways depending on the location
of the lesion.
✔ If the lesion is pulmonary the caseous focus can open to a bronchus
✔ A cavity then persists after the evacuation of the caseum
✔If the lesion is located under the skin or under a mucous membrane, the caseum is evacuated through an ulceration of the epithelium (ex: ulceration
of intestinal tuberculosis)
✔In the absence of external debridement, a fluctuating swelling occurs, clinically analogous to an abscess, but without pain or fever (cold abscess).
✔Calcification of the caseum The case which has not softened persists indefinitely in the body undergoing slow physico-chemical changes that lead to its calcification
✔This phenomenon is accompanied by a gradual decrease in the number of BK that persist in necrosis |
| How is histology of viral inflammation? | Virus-infested cells have a variable appearance in conventional histology:
Normal appearance: The viral antigen is however present and can be detected by immunohistochemistry or electron microscopy.
The cells may show "suffering" signs resulting in a cellular ballooning.
Sometimes there are viral inclusions: consisting of intra-cytoplasmic or intranuclear accumulation of viral proteins
✔ Intranuclear inclusions of cytomegalovirus
✔ Giant cells by fusion of histiocytic or epithelial elements (measles, herpes).
✔ Signs of viral infestation can be evidenced by some cytological
examinations: HPV on pap smear |
