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HMS Pathology > Chronic Inflammation and Repair > Flashcards

Chronic Inflammation and Repair Flashcards

1
Q

Scott Lovich’s Six Truly Essential Factors

A

IFN-γ

TNF-α

EGF

bFGF

VEGF

TGF-β

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2
Q

Goals of the chronic inflammatory response

A
  1. Neutralization of acute inflammatory cells and mediators
  2. activation of chronic inflammatory cells that drive subsequent healing responses
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3
Q

Chronic inflammation phase may last. . .

A

weeks to years

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4
Q

Acute inflammation is characterized by ____ infiltrate, while chronic inflammation is characterized by ____ infiltrate.

A

Acute inflammation is characterized by neutrophilic infiltrate, while chronic inflammation is characterized by mononuclear infiltrate.

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5
Q

Fibrosis

A

The proliferation of fibroblasts and accumulation of excess extracellular matrix

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6
Q

Inflammation Diagram

A
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7
Q

Chronic inflammation normally follows acute inflammation as part of the healing process, but may also be triggered by _____.

A

Chronic inflammation normally follows acute inflammation as part of the healing process, but may also be triggered by recurrent bouts of acute epithelial injury which interrupt the resolution process, resulting in a lesion characterized by concurrent acute and chronic inflammation.

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8
Q

Forms of injury which circumvent acute inflammatory responses in favor of chronic inflammatory responses

A

Viral infections (due to the location of the pathogen)

Persistent infections (typically mycobacteria, syphilis, and certain fungi)

Prolonged exposure to toxic agents (such as silica)

Autoimmune disease (like in rheumatoid arthritis)

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9
Q

Abscess formation

A

Occurs in the setting of certain bacterial or fungal infections (these organisms are then said to be pyogenic, or “pusforming”). Damage is directly caused by the growing micro-organisms and/or by recruited neutrophils releasing their toxic metabolites. Eventually, this mass of necrotic material will become a scar.

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10
Q

Inflammation flowchart

A
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11
Q
A

Acute lung inflammation

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12
Q
A

Chronic lung inflammation

Note that the alveolar walls have been lost

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13
Q

Once monocytes migrate into tissues and differentiate into macrophages, they may live for ____.

A

Once monocytes migrate into tissues and differentiate into macrophages, they may live for the entire lifetime of the organism.

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14
Q

major basic protein

A

Protein found in eosinophil granules. Highly cationic protein that is toxic to parasites but also causes epithelial cell lysis.

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15
Q

Timeline of inflammation phases for typical response

A
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16
Q

Regeneration phase

A

Characterised by development of blood vessels and granulation tissue, as well as regeneration of parenchyma if the parenchyma responds to growth factors produced by macrophages. These factors induce stem cell proliferation and differentiation into parenchymal cells.

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17
Q

The acute-to-chronic Inflammation transition

A
  1. Change in mediator predominance (spontaneous NO and eicosanoid decay, lipid mediator class switching, catalysis of other mediators, scavenging of inflammatory mediators and ROS, production of anti-inflammatory and pro-resolving factors)
  2. Shift from M1 to M2
  3. Efferocytosis of apoptosing neutrophils by macrophages
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18
Q

Major families of chemokines

A

CC anc CXC

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19
Q

Monoctyes display receptors for ___ chemokines. Neutrophils display receptors for ___ chemokines.

A

Monoctyes display receptors for CC chemokines. Neutrophils display receptors for CXC chemokines.

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20
Q

Macrophage activation

A
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21
Q

IFN-γ

A

The major cytokine responsible for macrophage activation is IFNγ, which is produced by activated Th1 lymphocytes (as well as cytotoxic T cells and NK cells).

  • Inhibiting viral replication
  • Driving Ig class switching
  • Driving T cell differentiation
  • Activating NK cells
  • Activating inducible nitric oxide synthase
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22
Q

Factors produced by repair-phenotype macrophages

A
  • Acid and neutral proteases to digest and remodel extracellular matrix
  • Complement components and coagulation factors. Hepatocytes are the major source of these proteins in plasma, but activated macrophages are the major producers locally at sites of injury.
  • Reactive oxygen species and nitric oxide
  • Prostaglandins and leukotrienes
  • Cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNFα), as well as growth factors, drive proliferation of and extracellular matrix production by smooth muscle cells and fibroblasts
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23
Q

M1 vs M2

A
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24
Q

Granulomas will form if there is____ present causing chronic and unrelenting macrophage activation

A

Granulomas will form if there is large or persistent foreign body present causing chronic and unrelenting macrophage activation

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25
Granulomas often contain \_\_\_\_\_.
Granulomas often contain **giant cells**. These are simply macrophages that have fused their cytoplasm and become syncytia.
26
Types of body that may induce granulomas
* Foreign bodies (classical type, such as a suture) * Autoimmune disease * Intracellular bacteria, typically mycobacteria (e.g. TB, leprosy). In this scenario, the core of the granuloma will often be necrotic – we call this a necrotizing or caseating granuloma * Persistent infection with certain other pathogens
27
Caseating granuloma should immediately implicate \_\_\_\_.
Caseating granuloma should immediately implicate **leprosy or tuberculosis**.
28
Effector functions of active macrophages
29
TNF-α
**TNFα** plays a critically important role in macrophage effector function. It is **produced by activated macrophages** (and some other cell types), and is a major mediator of the systemic effects known as **acute phase responses**, which include **fever, lethargy, and anorexia**. It also induces **hepatic synthesis of acute phase proteins**, including complement and coagulation factors. **IL-1** has very similar (**overlapping**) functions with TNFα. * Promoting vasodilation (may result in shock in extreme cases) * Promoting neutrophil release from bone marrow * Activating endothelium * Activating fibroblasts to proliferate and produce extracellular matrix
30
Regeneration refers to \_\_\_\_\_, while replacement refers to \_\_\_\_\_.
Regeneration refers to **regeneration of the parenchyma**, while replacement refers to **generation of connective tissue to fill gaps and support surrounding tissue**.
31
In order for regeneration to occur, . . .
1. **Injury must be limited**. There must be something to regenerate from. 2. **Parenchymal cells must either be labile or stable**. **Labile cells** are cells that **continue to proliferate** (e.g. most epithelia), while **stable cells** are cells that have **stopped dividing but retain the capacity to do so** 3. **ECM scaffolding must be preserved**.
32
Growth factors required for regeneration
Mostly secreted by **M2 macrophages** (**EGF, TGF-α, VEGF, IL-1, PDGF**) or present in the **ECM** (**bFGF/heparin, TGF-β**).
33
EGF
**EGF** (epidermal growth factor) is a particularly critical growth factor in tissue regeneration. Has many overlapping functions with **transforming growth factor alpha (TGF-α)** It is primarily **synthesized by activated macrophages** (and to a much lesser extent by epithelial cells), and is **mitogenic for both epithelial cells and fibroblasts**. As a result, it mediates not only regeneration, but also **fibroblast migration and proliferation**
34
The components of ECM required for tissue regeneration include ____ and \_\_\_\_.
The components of ECM required for tissue regeneration include **fibrous structural proteins (collagens and elastin)** and **adhesive glycoproteins (fibronectin and thrombospondin)**.
35
If an intact ECM scaffold is not present, then no matter what soluble growth factors are floating around, ____ will result.
If an intact ECM scaffold is not present, then no matter what soluble growth factors are floating around, **scar** will result.
36
Cell-ECM interaction diagram
37
Forming granulation tissue and scar
1. First, **macrophages and any leftover neutrophils break down the existing tissue** 2. **Angiogenesis occurs**, resulting in local vasculation. 3. **Fibroblasts migrate and proliferate** into the area of angiogenesis 4. **Extracellular matrix deposition occurs**, as a result of both increased synthesis and decreased degradation of ECM components 5. **Finally, extracellular matrix remodeling occurs** to result in **formation of a compact scar**. This results in **wound contraction**; the scar that finally forms may be less than 10% of the volume of the original injured tissue!
38
Granulation Tissue
39
Granulation tissue consists of. . .
**Loose, edematous extracellular matrix** with **lots of capillaries**, often **engorged with blood** (creating a hemorrhagic appearance), and **interspersed inflammatory cells** (residual chronic inflammation). The blood vessels are **new, delicate vasculature** that has formed as a result of angiogenesis. Its function is to serve as a **scaffold for scar formation**
40
Steps of angiogenesis
41
Endothelial cells proliferate, mature, and migrate in response to \_\_\_\_.
Endothelial cells proliferate, mature, and migrate in response to Endothelial cells proliferate, mature, and migrate in response to **VEGF and bFGF produced at the site of injury**.
42
During the process of angiogenesis in granulation tissue, the endothelium is \_\_\_\_.
During the process of angiogenesis in granulation tissue, the endothelium is **leaky**. This leaky endothelium **facilitates the diffusion of nutrients** over the poorly vasculated area.
43
bFGF (basic fibroblast growth factor)
**Produced by macrophages** (as well as endothelial and smooth muscle cells), and is **mitogenic for endothelial and smooth muscle cells**. It **induces remodeling** (synthesis and degradation) **of basement membrane and extracellular matrix**. bFGF is **produced in an inactive** **form** which is **bound to heparin** **in the extracellular matrix**. **Upon injury, proteases release it from heparin, and it becomes active.**
44
VEGF (vascular endothelial growth factor)
Synthesized by **activated macrophages**, as well as epithelial and tumor cells. Facilitates endothelial growth and vasculation.
45
Trichrome stain of granulation tissue
46
Trichrome stain of scar
47
TGF-β
TGFβ (transforming growth factor beta) is the **major mediator responsible for extracellular matrix synthesis and deposition**. It also **downregulates matrix metalloprotease activity**, and **inhibits T cell and macrophage activation.** TGFβ is **produced in inactive** form by activated macrophages, T cells, smooth muscle cells, and endothelial cells, and is**activated at sites of inflammation by proteolysis and other means**. The end result of its function is to **shut off the inflammatory response** and **promote fibrosis**. **It is the major factor responsible for fibrosis and its clinical consequences (scarring, cirrhosis, etc).**
48
The transition from chronic inflammation to fibrosis (scarring) is accomplished through regulated activity of \_\_\_\_\_.
The transition from chronic inflammation to fibrosis (scarring) is accomplished through regulated activity of **matrix metalloproteases**
49
How matrix metalloproteases regulate fibrosis
50
collagenases and stromelysins
Common matrix metalloproteases. **Produced by M2 macrophages and activated fibroblasts**. **Activated by proteolytic cleavage, acidic conditions, or ROS/free radicals.**
51
EGF, IL-1, and TNF-α effects on fibroblasts
In the setting of chronic inflammation, the balance of mediators results in **fibroblast stimulation**. This causes increased **proliferation of fibroblasts**, and **synthesis and activation of MMPs**. As a result, ECM is broken down, fibroblasts migrate into the site of injury, and deposition of granulation tissue can occur
52
Complex role of steroids in scar formation
Steroids **inhibit macrophage activation** (among many other functions), and **activated macrophages produce mediators that both stimulate and inhibit fibroblasts**. Overall, however, the **net effect of steroids is to reduce fibrosis** and **inhibit scarring** (this is why steroid creams are used by plastic surgeons to achieve a “younger” look).
53
Tissue inhibitors of metalloproteases
Produced by most mesenchymal cells. These molecules **regulate fibrosis by blocking degradation of ECM under physiologic (non-injury) conditions.**
54
Summary of wound healing mediators
55
Peak acute inflammation is ____ hours after injury.
Peak acute inflammation is **~****24** hours after injury.
56
Healing by primary and secondary intention
57
myofibroblasts
Cells with functionality of both smooth muscle cells and fibroblasts. Primary agents of wound contracture.
58
organization
The process of forming granulation tissue
59
Fibrous adhesions
Bands of fibrous tissue that may be formed within or between organs as a result of wound healing. May produce obstructions or ischemia in severe cases.
60
\_\_\_\_\_\_ today are the #1 cause of bowel obstruction, exceeding hernias and cancer.
**Post-surgical (iatrogenic) adhesions** today are the #1 cause of bowel obstruction, exceeding hernias and cancer.

HMS Pathology (7 decks)

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