Barrier Organs exam preparation

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Previous exam 2023

1. Barrier organ - general

Name two physical barrier functions each of A) the respiratory epithelium, B) the epidermis (skin), and C) the gastrointestinal mucosa, respectively, and briefly describe their properties. D) Briefly describe the major differences between these physical barriers

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A)Respiratory epithelium
1. Mucociliary Clearance. Goblet cells produce mucus that traps particles and pathogens, while cilia move the mucus toward the throat for removal.
2. Sensory function. Olfactory epithelium is structurally adapted to perform its function as sensing smell.

B) Epidermis (skin)
1. Physical barrier. Stratum corneum and cell-cell junction in epidermis form a tough physical barrier which protects the body from the external environment
2. Prevents water loss. The epidermis layer regulates the amount of water released from the body into the atmosphere through transepidermal water loss.

C) Gastrointestinal mucosa.
1. Protective function. The gastrointestinal mucosa forms a barrier between the body and luminal environment which not only contains nutrients but also is laden with potentially hostile microorganisms and toxins.
2. Absorption function. Gastrointestinal mucosa can absorb water, electrolytes and nutrients.

D) Major Differences Between Physical Barriers
Respiratory Epithelium: Focuses on particle clearance through mucus and cilia.
Epidermis: A robust, dry external barrier designed for environmental protection.
Gastrointestinal Mucosa: A moist, dynamic barrier emphasizing nutrient absorption while managing pathogen exposure.

From ChatGPT, slides, google, text book

2. Barrier organ - general

Describe two general mechanisms for chemical effects on epithelial barriers and their potential adverse outcomes

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General Mechanisms for Chemical Effects on Epithelial Barriers  

1. Disruption of Tight Junctions  
   - Mechanism: Chemicals (e.g., heavy metals, detergents) can weaken or disrupt tight junction proteins (e.g., occludins and claudins) that seal epithelial cells.  
   - Adverse Outcomes: Increased permeability allows pathogens, allergens, or toxins to penetrate, leading to inflammation, infections, or systemic toxicity.

2. Oxidative Stress  
   - Mechanism: Reactive chemicals or their metabolites generate reactive oxygen species (ROS), damaging cell membranes, proteins, and DNA.  
   - Adverse Outcomes: Epithelial cell death, impaired barrier repair, chronic inflammation, or cancer development.

From ChatGPT

3. Barrier organ - lung

In respiratory toxicology there are several factors which determines the level of toxicity. Specify at least four.

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Factors Determining the Level of Toxicity in Respiratory Toxicology  

1. Particle Size and Solubility  
   - Smaller particles (e.g., nanoparticles) penetrate deeper into the respiratory tract. Soluble particles dissolve and exert effects locally or systemically.

2. Chemical Reactivity  
   - Highly reactive substances (e.g., ozone, nitrogen oxides) can cause oxidative damage to lung tissues.

3. Exposure Duration and Concentration  
   - Prolonged or high-concentration exposure increases cumulative damage to the respiratory epithelium.

4. Host Factors  
   - Age, pre-existing conditions (e.g., asthma), genetic susceptibility, and immune status influence toxicity levels.

From ChatGPT

4. Barrier organ - lung

Glucocorticoids are used to treat asthma. Briefly explain how they work and describe at least two major toxicological effects that could be observed with overuse.

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How they work:
First of all, glucocorticoids diffuse across cell membrane and bind glucocorticoid receptors. This causes dissociation of chaperone proteins allowing translocation of glucocorticoid receptor to nucleus. In nucleus, glucocorticoid receptor can dimerize and bind to glucocorticoid response elements in promoter regions of steroid-responsive genes which can switch on (or off) gene transcription. Or GR can bind other transcription factors as a monomer, and thereby switch off genes activated by such transcription factors. Therefore, treat asthma through general anti inflammation.

Toxicological effects:
1. Osteoporosis
2. Infections
3. Cushingoid Features

From slides

5. Barrier organ - lung

Why can’t current in vitro exposure systems replace airway exposure animal models yet? Briefly describe 3 reasons

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Reasons In Vitro Exposure Systems Can’t Fully Replace Animal Models in Airway Toxicology  

1. Complex Physiology  
   - In vitro models lack the integrated physiological responses of the whole organism, such as immune system interactions and systemic effects.  

2. Dynamic Exposure Conditions  
   - Airway exposure in animals accounts for airflow, breathing patterns, and particle deposition, which are challenging to replicate accurately in vitro.  

3. Chronic and Long-term Effects  
   - In vitro systems are limited in studying chronic exposure or disease progression over time, unlike animal models that can mimic long-term outcomes.

From ChatGPT

6. Barrier organ - skin

Name three types of cells which are involved in the maintenance of skin homeostasis, and describe the mechanisms by which each of them contribute to homeostasis

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Cells Involved in Skin Homeostasis  

1. Keratinocytes  
   - Mechanism: Form the epidermis by producing keratin, creating a physical barrier to protect against environmental insults and preventing water loss.

2. Melanocytes  
   - Mechanism: Produce melanin to protect skin from UV radiation by absorbing harmful rays and preventing DNA damage in keratinocytes.

3. Langerhans Cells  
   - Mechanism: Act as antigen-presenting cells in the immune system, detecting pathogens and initiating immune responses to maintain skin defense.

From ChatGPT

7 Barrier organ - skin

What are the benefits of a healthy skin microbiome, and what can damage the skin microbiome? Give two examples of each, including a brief description

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Benefits:
1. Protection against pathogen invasion. Some skin microbiome can degrades proteins involved in biofilm formation, or inhibits others bacterial growth, or synergize with keratinocyte derived antimicrobial
peptides.
2. Induction of immune tolerance. Early-life exposure to microbes promotes the development of immune tolerance. If priming for immune tolerance has not occurred, encounter of microbial species later in life leads to effector T cell driven immune responses

Factors That Can Damage the Skin Microbiome  
1. Lifestyle  
   - Excessive use of soaps and sanitizers eliminates both harmful and beneficial microbes, disrupting microbial balance.  
2. Broad-spectrum Antibiotics  
   - Oral or topical antibiotics can indiscriminately kill skin bacteria, reducing microbial diversity and resilience.

Benefits from slides, factors from ChatGPT

8. Barrier organ - skin

A) Briefly describe how to perform an in vivo experiment in humans with the objective to measure uptake of chemicals such as pyrimethanil via the skin. B) How can carriage of the filaggrin gene copy number variant (CNV) 12 influence the uptake?

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## 9. Barrier organ - GI

**Hierarchical stem cell model at intestinal homeostasis. A) State which cell type in the intestine that gives rise to all differentiated intestinal epithelial cell types, and where these cells are located during homeostasis. B) Name four types of differentiated intestinal epithelial cells C) Describe the function of two of the differentiated cell types and how they may be involved in- or be targets of intestinal toxicity.**

![image-20241128153736552](./images/image-20241128153736552.png)

A) LGR5+ intestinal stem cell. In the bottom of Crypt.
B) Goblet cell, Tuft cell, Paneth cell, Absorptive enterocytes
C) Functions and Roles in Intestinal Toxicity

Enterocytes
Function: Absorb nutrients and water, form the primary barrier against pathogens and toxins.
Toxicity Involvement: Targeted by toxins like lipopolysaccharides, leading to compromised nutrient absorption and increased intestinal permeability.

Goblet Cells
Function: Secrete mucus to protect the epithelial surface and facilitate the passage of contents.
Toxicity Involvement: Reduced mucus production due to chemical damage can increase susceptibility to pathogens and abrasive injuries.

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From ChatGPT



## 10 Barrier organ - GI

**A) Briefly describe how the immune system reacts to an intestinal injury, B) how the tissue damage is resolved, and C) what the main role of the aryl hydrocarbon receptor (AHR) is during the tissue regeneration**

A) In acute inflammatory responses, rapid recruitment of
granulocytes (ie, neutrophils, eosinophils, and basophils) to the inflammatory site occurs. Neutrophils then secrete antibacterial proteins (eg, of
the S-100 family), myeloperoxidase, tissue-degrading
enzymes, and reactive oxygen species, leading to an
oxidative burst reaction to destroy microbes.
B)
Inflammation Dampening: In order to resolve inflammation, lipoxins, resolvins, and other resolution mediators are recreted, and regulatory immune cells helps to resolve inflammation.

Epithelial Regeneration: Induced by growth factors such as epidermal growth factor (EGF), intestinal stem cells (e.g., Lgr5+ cells) proliferate and differentiate to replace damaged epithelial cells, restoring barrier function.

C) AHR is required for differentiation of intestinal stem cells upon tissue damage. Also, AHR drives termination of colonic epithelial regeneration.

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From slides and ChatGPT



# Example Questions from Emma

## 1) Name two physical barrier functions each of A) the respiratory epithelium, B) the epidermis (skin), and C) the gastrointestinal mucosa, respectively, and briefly describe their properties, as well as major differences between these physical barriers

The same as 2023.



## 2) Briefly describe three possible absorption paths for chemicals penetrating the stratum corneum.

  1. Intercellular Lipid Pathway
    Chemicals diffuse between corneocytes (dead keratinized cells) through the lipid matrix.
    This is the primary route for lipophilic (fat-soluble) molecules due to the lipid-rich environment. Slow and tortuous due to the complex lipid structure, but it accounts for most chemical penetration.

  2. Transcellular Pathway
    Chemicals pass directly through the corneocytes, crossing both hydrophilic (cell interiors) and lipophilic (lipid bilayers) regions.
    Requires molecules to have both water and lipid solubility. It is less common due to the structural barriers.

  3. Appendageal Pathway
    Chemicals penetrate through skin appendages, such as sweat glands or hair follicles.
    It can help chemicals bypass the dense stratum corneum, playing a minor role but important for larger or polar molecules that struggle with the lipid matrix.

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    From Xiyuan



    ## 3) A) Give one example of skin toxicity, B) state at least 2 agents which can cause the toxicity, and C) briefly describe the underlying immunological/toxicity mechanism(s) leading to the chosen pathology.

    A) Example of Skin Toxicity
    Irritant Contact Dermatitis (ICD): A non-immune-mediated inflammatory response caused by direct damage to the skin from irritants.

B) Agents That Can Cause ICD
Detergents (e.g., sodium lauryl sulfate): Found in cleaning products and personal care items.
Acids or Alkalis: Industrial chemicals such as hydrochloric acid or sodium hydroxide.

C) Mechanism Leading to ICD
Direct Damage:
The irritant damages keratinocytes and disrupts the skin barrier, allowing irritants to penetrate deeper into the epidermis. Damaged keratinocytes release inflammatory mediators, such as IL-1α, IL-6, and TNF-α.

Inflammatory Response:
Released cytokines and chemokines recruit immune cells (e.g., neutrophils and macrophages) to the site of damage.
This leads to acute inflammation, causing redness, swelling, burning, and scaling.

Chronic Exposure:
Repeated exposure may impair the skin’s ability to repair itself, leading to chronic inflammation and thickening of the skin.

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From Xiyuan



## 4) State which cell type in the intestine that gives rise to all differentiated intestinal epithelial cell types, and where these cells are located during homeostasis.

The same as 2023.



## 5) Why can’t current in vitro exposure systems replace airway exposure animal models yet? Briefly describe 2 reasons

The same as 2023.



## 6) A) Describe what dysbiosis means, B) how chemicals may cause dysbiosis at the GI barrier, and C) potential local versus systemic consequences of gut dysbiosis.

Dysbiosis refers to an imbalance in the composition, diversity, or function of the gut microbiota, where harmful microbes dominate or beneficial microbes decrease. This disruption can affect host health and lead to various diseases.

Chemicals can disrupt gut microbiota by:
Direct Microbial Toxicity:
Antibiotics, pesticides, or heavy metals can kill beneficial bacteria or inhibit their growth, altering the microbiota’s balance.
Disruption of Gut Barrier Integrity:
Chemicals like nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol can increase intestinal permeability (“leaky gut”), allowing pathogens or toxins to cross the epithelial barrier.
Alteration of Microbial Metabolism:
Certain chemicals, such as artificial sweeteners, can modify bacterial metabolism, favoring the growth of harmful species like opportunistic pathogens.

Local Consequences:
Increased Gut Inflammation:
Dysbiosis can stimulate excessive immune responses due to the overgrowth of pathogenic bacteria producing pro-inflammatory signals (e.g., lipopolysaccharides, or LPS).
Impaired Nutrient Absorption:
Disrupted microbiota can reduce production of short-chain fatty acids (SCFAs) like butyrate, essential for gut health and energy.

Systemic Consequences:
Chronic Inflammation:
Dysbiosis-induced gut permeability allows bacterial toxins (e.g., LPS) to enter the bloodstream, triggering systemic inflammation and potentially contributing to diseases like metabolic syndrome, cardiovascular disease, or autoimmune disorders.
Neurological Effects:
The gut-brain axis may be affected, leading to mood disorders, anxiety, or neurodegenerative diseases (e.g., Parkinson’s).
Immune Dysregulation:
A disrupted microbiota can impair immune system function, increasing susceptibility to infections or allergies.

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From Xiyuan



# Previous questions

## 1. Briefly outline three types of non-immune, non-specific defense mechanisms present in epithelial surfaces against the invasion of pathogens or toxic substances(2p).

Non-Immune, Non-Specific Defense Mechanisms on Epithelial Surfaces

  1. Physical Barriers

    • Tight junctions between epithelial cells prevent the entry of pathogens and toxins by forming a continuous protective layer.

  2. Chemical Secretions

    • Antimicrobial peptides (e.g., defensins) and enzymes (e.g., lysozyme) secreted by epithelial cells neutralize or destroy invading microbes.

  3. Mucus Production

    • Mucins secreted by goblet cells trap pathogens and toxic particles, preventing them from directly contacting epithelial surfaces.
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      From ChatGPT



      ## 2. The fluid lining of the alveolar surface includes surfactants. What is it, and what is its purpose in the lungs? (2p)

      Surfactant in the Lungs

  • What It Is: Pulmonary surfactant is a lipid-protein complex primarily composed of phospholipids and surfactant proteins, secreted by alveolar type II cells.

  • Purpose in the Lungs:

    1. Reduce Surface Tension: Lowers the surface tension at the air-liquid interface in the alveoli, preventing alveolar collapse during exhalation (atelectasis).
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      # New words

      Stratum corneum
      keratinocytes
      Melanocytes
      Langerhans
      granulocytes
      neutrophils
      enterocytes
      chaperone
      Osteoporosis
      Cushingoid Features
      Appendageal
      Irritant Contact Dermatitis