Lecture 11: Chronic Inflammation Flashcards
How can chronic inflammation arise?
- From prior acute inflammation which failed to resolve
2. From prior acute inflammation which may have had distinctive properties of chronic inflammation almost from the onset
Name the three different types of causes of chronic inflammation
- Persistent exposures
- Abnormal immune responses
- Novel tissue
What are two examples of persistent exposures which can cause chronic inflammation
Irritants like bronchitis, emphysema (smoke)
Infections like HBV, H. Pylori, M. Tuberculosis
What are three examples of abnormal immune redness that can cause chronic infection
Harmless environmental agents like allergies
Commensal microbes like in inflammatory bowel disease: Crohn’s
Components of the body like autoimmune diseases
What are two examples of novel tissue that can cause chronic inflammation
Wounds that do not heal, like cancers
Grafts, like rejection of organ transplants
What is acute inflammation mediated by?
Cells of the innate immune system
What does chronic inflammation also require?
Cells of the adaptive immune system
How are circulating monocytes recruited into tissues?
By chemotactic stimuli
What happens after monocytes are recruited into tissues?
They differentiate into macrophages
What happens to macrophages in innate immunity?
They phagocytose unwanted tissue (debris, oxidised lipoprotein) or microbes
They kill bacteria
They regulate inflammation, angiogenesis and repair
How do macrophages regulate inflammation angiogenesis and repair?
They release
ROS, cytokines(IL-1β, TNF, IL-6) and chemokines
They release proteases like MMPs that remodel ECM
How do macrophages regulate adaptive immunity?
Acting as antigen presenting cells
Macrophages may also sustain what?
Chronic inflammation
What can antigen presenting cells do?
Engulf microbes or their products
Process them to peptide fragments
Present peptides to lymphocytes
Lymphocytes have a vast repertoire of receptors that recognise what?
Epitopes on macromolecules
What are epitopes
Specific molecular shapes
What happens when epitopes are recognised as foreign?
Lymphocytes will generate immune response
Helper cell populations are a part of what class of lymphocytes?
T lymphocytes
What do T helper cells do?
Secrete cytokines to regulate cells of innate and adaptive immunity
What type of cytokine does TH-1 cell secrete?
Interferon-γ
What does interferon -γ do?
Stimulates TH1 development and activates macrophage responses to intracellular pathogens
Abnormal responses of activated by IFN-γ mediate what?
Autoimmunity
What type of cytokine do TH2 cells secrete?
IL-4 and IL-21
What does IL-21 do?
Stimulates TH17 development
Activates epithelial responses to microbes
What are some epithelial responses to microbes which are activated by TH-17 development?
Secretion of anti microbial peptides (AMPs) like defensins and GM-CSF which recruits neutrophils
What do abnormal responses mediate?
autoimmunity
What do Treg cells secrete?
cytokines such as TGFβ
What does TGFβ stimulate?
Treg development suppresses inflammation (i.e. as a fire extinguisher of other T helper activities)
What does deficient Treg function lead to?
excessive inflammation
What are some epithelial responses to microbes which are activated by TH-17 development?
Secretion of anti microbial peptides (AMPs) like defensins and GM-CSF which recruits neutrophils
What do abnormal responses mediate?
autoimmunity
What do Treg cells secrete?
cytokines such as TGFβ
What does TGFβ stimulate?
Treg development suppresses inflammation (i.e. as a fire extinguisher of other T helper activities)
What does deficient Treg function lead to?
excessive inflammation
What do B cells differentiate into?
Plasma cells
What do plasma cells produce?
Antibodies
What are antibodies?
Proteins that bind to particular epitopes on target molecules
What are particular epitopes on target molecules also known as?
Antigens
What is GERD?
Gastroesophageal reflex disease
What is GERD marked by?
Chronic mucosal inflammation
How many adults in western countries does GERD affect?
20-30%
What are some symptoms of GERD
Heart burn
Regurgitation of stomach contents
Dyspepsia (upper abdominal pain)
GERD arises from regurgitation of stomach fluid containing what things?
Acid, proteases, bile acids
What is regurgitation of stomach acid treated with?
Proton pump inhibitors like omeprazole
What are two examples of proteases that can be found in regurgitation of stomach fluid?
Pepsin and trypsin
What can bile acids in regurgitation of stomach fluid cause?
Mitochondrial damage,
Oxidative stress
DNA breaks
What condition may GERD progress to
Barrett’s oesophagus
What is the progression from GERD to barrett’s oesophagus caused by?
Squamous, to columnar, to intestinal (goblet cell) metaplasia
Native epithelial cell types can’t cope with stressful conditions caused by regurgitation of stomach acid, so they are replaced with intestinal cells which produce mucin
What do mice express, in the transgenic mice model which outlines the steps involved in barrett’s oesophagus condition?
The human IL-1β from an oesophagus specific promotor
What does expression of IL-1β lead to?
Inflammation with erythema and oedema
Immature myeloid cell, neutrophil, TH1 cells and macrophage recruitment
Barrett’s oesophagus with columnar epithelium- inflammatory environment requires epithelial stem cells from stomach
Dysplasia and cancer
What do immature myeloid cells secrete
IL-6
What does secretion of IL-6 from immature myeloid cells promote?
Survival and proliferation of epithelial cells
Along with columnar epithelium, what else is secreted in metaplastic barrett’s oesophagus
Intestinal epithelial homeobox protein CDX2
Mucin
Microvilli
What are the changes which occur due to expression of IL-1β potentiated by?
Bile acids,
DNA alkylators like N-nitroso compounds
Where do N-nitroso compounds originate from?
Dietary nitrate is reduced to NO by gastric fluid, forming N-nitroso compounds
What is barrett’s oesophagus a risk for?
Oesophageal cancer
What is the conversion rate of barrett’s oesophagus to oesophageal cancer?
0.5-1.0%
How much has the incidence of oesophageal cancer increased in western countries in the last 50 years?
Incidence has increased five fold
What are the five spectrum of pathologies associated with chronic gastritis
Chronic superficial gastritis
Peptic ulcers
Atrophic gastritis
Intestinal metaplasia
Dysplasia
What is chronic superficial gastritis
When the are presence of inflammatory cells and products
What are peptic ulcers
The occurrence of the destruction of the epithelium and underlying stroma
What is atrophic gastritis
The loss of gastric glandular epithelium with goblet cells
What is intestinal metaplasia
The replacement of intestinal epithelium with goblet cells
What is dysplasia
The loss of normal tissue differentiation that may proceed to cancer
Which microorganism is the cause of the pathological spectrum of diseases associated with chronic gastritis
Helicobacter pylori
How did Warren and Marshall illustrate the cause of those diseases?
-observed spiral bacteria assoc. with inflamed epithelium as a new species and named: H. pylori
-hypothesised as cause of ulcers despite other assumptions of H. pylori being incidental contaminants
-discovered H. pylori grew slowly (from cultures left over an Easter weekend)
- Marshall drank a flask full of pylori to prove its cause of gastritis.
Discovered bacteria turned off acid secretion he did not taste acid in his vomit
- proved that disease was from bacterial infection. However gastroenterologists initially resist evidence of successful treatment by antibiotics
What percentage of humanity do H. pylori infect?
50%
Where do H. pylori live?
Under mucus layer or inside epithelial cells
Which toxins do H. pylori inject into cells?
cagA and peptidoglycan
What else do H. pylori release?
H. pylori-neutrophil activating protein (HP-NAP)
What does cagA do?
Disassembles tight junctions, leading to
- loss of cell polarity,
- motile behaviour, and
- disruption of epithelial integrity
What do cagA and PG do?
Induce gastric epithelial cells to secrete IL-8 , which recruits neutrohils
How does cagA and PG induce GE cells to secrete IL-8?
They act through pattern recognition receptors and transcription factor NF-κB
What does HP-NAP do?
Induces neutrophils to release damaging ROS and myeloperoxidase
What other inflammatory cell does HP-NAP recruit?
Macrophages
What do the recruitment of macrophages by HP-NAP release?
IL-8 and IL-1β
How are parietal cells maintained?
By secreting acid,
This increases intracellular Ca2+ and sustains the expression of sonic hedgehog
What type of protein is sonic hedgehog?
Morphogenic protein
What does IL-1β do?
It suppresses acid secretion, intracellular Ca2+ and sonic hedgehog expression with loss of parietal cells with metaplasia
What is loss of cells known as?
Atrophy
Which two diseases fall in the category of inflammatory bowel disease?.
Crohn’s disease
Ulcerative colitis
When does Crohn’s disease first appear?
Adolescents or young adults
Where does Crohn’s disease mainly occur
In the end of the ileum, or beginning of the colon, but it can occur anywhere in the gut
What happens in Crohn’s disease?
- Affected areas become inflammaed
- Epithelial lining ulcerated
- Wall of bowel may undergo extensive damage and fibrotic thickening
- Lumen narrows with obstruction
- Fissures develop through bowel wall and drain into pus filled cavities or form channels into nearby loops of bowel
- Immune system is activated, lymphocytes and macrophages aggregate and lymph nodes are enlarged
- Probability of developing cancer is increased
What are the effects of areas of inflammation in Crohn’s disease?
Redness, swelling, pain, leukocyte infiltrate
What are fissures?
Cracks
What are abscesses.
Pus filled cavities
What are fistulas?
Channels formed from abscesses
What are follicles?
Aggregated lymphocytes
What are granulomas?
Aggregated macrophages
List the aetiological factors implicated in Crohn’s disease
Family history
Environmental factors
Microbial factors
Immune responses
How has family history been known to implicate Crohn’s disease?
Concordance in twins & siblings suggests genetic contribution
30% of Caucasians with Crohn’s have a CARD15 gene mutation
What is the CARD15 protein?
It is a astern recognition receptor for bacterial products
It helps innate immune system to eliminate bacteria
What are some environmental factors which have contributed to Crohn’s disease
Diet, NSAIDs, tobaccos, increased hygiene
How is increased hygiene an environmental factor that may result in Crohn’s?
Increased hygiene alters the balance of commensal microbes
How are microbial factors implicated in Crohn’s disease?
Microbial factors include pathogenic infections as triggers
Altered communities of commensal Bactria may alter ecology of gut
How are uncontrolled immune responses an implication in Crohn’s?
Over active TH1 cells or under active Treg cells can result in uncontrolled immune responses which towards commensal bacteria
This damages the bowel
What is the suggested outline of the pathogenesis of Crohn’s
- environmental trigger damages mucosa
- damage (with bacterial invasion of the wu mucosa) induces inflammatory response and repair
- those with genetic deficiency in innate immunity or barrier function unable to repair damage or eliminate microbes from wu mucosa
- uncontrolled T cell responses develop against commensal bacteria and long term damage occurs to the colon wall
