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Pathology of inflammation 2024 LEC 3 ‫د‬.‫ايمان سعود خليفة‬ Systemic effects of inflammation: Fever (pyrexia).1 2. Increased level of acute phase 4.proteins Other 3. Leukocytosis manifestations (high W...

Pathology of inflammation 2024 LEC 3 ‫د‬.‫ايمان سعود خليفة‬ Systemic effects of inflammation: Fever (pyrexia).1 2. Increased level of acute phase 4.proteins Other 3. Leukocytosis manifestations (high WBC count) :Fever (pyrexia).1 Fever, characterized by an elevation of body temperature, usually by 1°C to 4°C, is one of the most prominent manifestations of the acute- phase response, especially when inflammation is associated with infection. :Mechanism of fever Substances that induce fever are called pyrogens and include bacterial products (exogenous pyrogens, e.g., LPS) and cytokines, principally IL-1 and TNF (called endogenous pyrogens). These pyrogens stimulate production of Prostaglandins locally at thermoregulatory center within hypothalamus to induce.fever :Increased level of acute phase proteins.2 These are plasma proteins synthesized in the liver, e.g..fibrinogen, C-reactive proteins High level of fibrinogen will stimulate RBC agglutination which is result in high level of ESR in inflammation. :Leukocytosis (high WBC count).3 Normal WBC count is 4000 – 11000 cells per.microliter Leukocytes count is typically increased in inflammation (bacterial infection) may reach up.to 15000 – 20000 cells per microliter In some infection may reach to the level of 40000 or 100000 (this is called Leukemoid reaction) and this is similar to the white cell counts observed in leukemia, from which they must be distinguished This increased WBC count is due to accelerated release of.WBC from bone marrow in response to IL1 & TNF Most of bacterial infections induce neutrophilia (increased neutrophils) Most of viral infections are associated with lymphcytosis.Parasitic diseases induce eosinophila Certain bacterial infections like typhoid, T.B, protozoal infection cause leucopenia. 4. Other manifestations of the acute-phase response include decreased sweating, mainly because of redirection of blood flow from cutaneous to deep vascular beds, to minimize heat loss through the skin; chills , rigors (shivering), anorexia and malaise, probably because of the actions of cytokines on brain cells  Tissue Repair (healing): o Is the restoration of function & architecture of tissue after an injury. o Repair begins very early in the process of inflammation & involves two processes: 1. Regeneration of injured tissue by parenchymal cells of the same type. 2. Replacement of injured tissue by connective tissue (fibrosis & scarring). Commonly, tissue repair involves a combination of both processes. Regeneration required intact basement membrane (intact Extra Cellular Martrix), while if the basement membrane is destroyed then fibrosis & scarring will occur. Both regeneration & fibrosis are controlled by soluble growth factors. Cellular regeneration: According to regenerative capacity of cells, we have three types of cells in our body: 1. Labile cells: they are continuously dividing & continuously dying throughout their life, they are derived from stem cells & they are not enter the G0 phase of cell cycle. E.g. hematopoietic cells within bone marrow, surface epithelia (skin, GIT, genitourinary system, & glands). 2. Stable cells: They are quiescent in the G0 phase of cell cycle & have minimal replicative capacity in the normal state, but are capable of rapid division in response to injury. E.g. parenchymal part of solid organs (liver, pancreas, kidney), endothelail cells of blood vessels, fibroblasts & smooth muscles. 3. Permanent cells: They are remain permanently within the G0 phase of cell cycle ( have no replicative capacity), they are usually healed by fibrosis & scarring. E.g. neurons, cardiac & skeletal muscles Growth factors: The processes of regeneration & fibrosis are both under control of soluble growth factors.  They are polypeptides circulating in the blood or produced locally by the cells.  Most of growth factors have pleiotropic effect (stimulate cellular proliferation, cell migration, differentiation & tissue modeling).  These factors stimulate cells regeneration & fibrosis by stimulate the expression of proto oncogenes.  These factors are important also in development of cancers by affect alteration of proto oncogenes into oncogenes (genes responsible for development of cancer.) Types of effects of growth factors: 1. Autocrine effect: effect of growth factors on the cells that secrete them. 2. Paracrine effect: effect factors on the cells near or adjacent to it. 3. Synaptic effect: These effects are seen in the neural tissue & muscles by secrete specific neurotransmitters at synapses. 4. Endocrine effects: In which the growth factors enter the blood stream & reach the target cells. Examples of Growth factors: Epidermal growth factor (EGF). Platelets derived growth factor (PDGF). Fibroblast growth factor (FGF). Vascular endothelial growth factor (VEGF). Transforming growth factor (TGF-b). Cytokines (IL-1, TNF). Repair by connective tissue (Fibrosis): This type of repair occurs in severe tissue injury with damage to both parenchymal cells & to the basement membrane. Fibrosis consists of four parts: 1. Angiogenesis (new blood vessels formation). 2. Migration & proliferation of fibroblasts. 3. Deposition of ECM (EXTRACELLULAR MATRIX). 4. Maturation & reorganization of fibrous tissue. Stages of Repair by fibrosis: (by the time). 1. Repair begins within 24hrs of injury by replacement of non regenerating cells by fibroblasts & vascular endothelial cells. 2. By 3-5 days: formation of Granulation tissue (The hallmark of healing process): Gross features of granulation tissue: Pink, soft, granular Mic: small thin walled blood vessels, fibroblasts, edematous stroma & macrophages.  Granulation tissue Gross: Pink, soft, granular Mic.:small blood vessels, fibroblasts, edematous stroma & macrophages Fibrosis (scar formation): Builds on the granulation tissue framework & formed by two processes: 1. Emigration & proliferation of fibroblasts into the site of injury. 2. Deposition of ECM by these fibroblasts. These processes are controlled by growth factors (PDGF, b-FGF & TGF) derived from endothelial & inflammatory cells.  Deposition of ECM is includes mainly deposition of Collagen type III, which is then convert collagen type I by several weeks (responsible for strength of scar).  Then scarring will develop which consists of dense collage fibers, fragments of elastic tissue & inactive spindle shaped fibroblasts.  Then scar remodeling will occur by a balance between ECM synthesis & degradation. Wound healing: 1- Healing by first intention (primary union) 2-Healing by second intention Healing by first intention (primary union): This is the healing of a clean, uninfected wound with limited tissue loss e.g. surgical incision. Here the epithelial proliferation is predominates the fibrosis & the gap is filled by fibrin clot. Day 1: neutrophils present at edges of wound, basal layer of epidermis showing mitosis & epithelial cells migrating & meet from both sides to form thin continuous layer below the scab. Day 3-5 : Macrophages & granulation tissue appear at the incision site. Collagen at the edges of wound is vertical & not connects from both sides Day 5-7: - Angiogenesis. - Collagen bridges the wound. - Normal thickness of epidermis with keratinization. Second week: - Continuous collagen deposition. - decrease leucocytes infiltration, edema & vascularity. 1ST month; No inflammation, normal epidermis with permanent loss of skin appendages 2 months : wound reach its maximum strength (70% of normal unwound skin) Healing by second intention: Occur in wound with excess tissue loss e.g. infarction, ulceration. Differ from first intention: 1. More inflammation because of more tissue loss. 2. More granulation tissue inflammation. 3. Contraction phenomena (within 6weeks there is decrease in the size of the wound by myofibroblasts. Factors affect the wound healing: 1. Infection (delay wound healing because infection induces more tissue destruction). 2. Type (and volume) of tissue injured: complete healing occurs only with labile & stable cells. 3. location of injury: wound of the face healed faster than other site because of good blood supply. 4. Excess movement at site of wound will delay healing (wound at the joint). 5. Presence of foreign body: delay wound healing. 6. Nutritional causes: lack of proteins, vitamins C, zinc deficiency,decrease wound healing. 7. Diabetes mellitus, glucocorticoid hormone will block inflammatory response. 8. Vascular insufficiency: e.g. arterial occlusion ,decrease wound healing. Complications of wound healing: Complications in wound healing can arise from abnormalities in any of the basic components of the repair process. These complications can be grouped into three general categories: (1) deficient scar formation (2) excessive formation of the repair components (3) formation of contractures. 1- Inadequate formation of granulation tissue or assembly of a scar can lead to two types of complications: wound dehiscence and ulceration. Dehiscence or rupture of a wound is most common after abdominal surgery and is due to increased abdominal pressure. Vomiting or coughing, can generate mechanical stress on the abdominal wound. Wounds can ulcerate because of inadequate vascularization during healing. For example, lower extremity wounds in individuals with atherosclerotic peripheral vascular disease typically ulcerate Dehiscence or rupture of a wound 2- Excessive formation of the components of the repair process can give rise to hypertrophic scars and keloids. The accumulation of excessive amounts of collagen may give rise to a raised scar known as a hypertrophic scar; if the scar tissue grows beyond the boundaries of the original wound and does not regress, it is called a keloid. Keloid formation seems to be an individual predisposition, and for unknown reasons, it is somewhat more common in African Americans.  The accumulation of excessive amounts of collagen may result in a raised scar known as a hypertrophic scar Keloid. A, Excess collagen deposition in the skin forming a raised scar known as keloid. B, Note the thick connective tissue deposition in the dermis 3-Contraction in the size of a wound is an important part of the normal healing process. An exaggeration of this process gives rise to contracture and results in deformities of the wound and the surrounding tissues. Contractures are particularly prone to develop on the palms, the soles, and the anterior aspect of the thorax. Contractures are commonly seen after serious burns and can compromise the movement of joints Wound contracture. Severe contracture of a wound after deep burn injury Thank you