Appunti di Patologia (corso OMP)

Oncology and molecular pathology

4/10/2022

Exams: 6 questions -> 3 pathology, 2 oncology, 1 neuropathology.

We have 2 hours; additional points from the midterm test or multidisciplinary research essay.

Inflammation

Inflammation is not a disease but a physiological response to restore the normal conditions. The effects could become a disease. Ex. Cold.

Cytokines

Cytokines are the mediators of inflammation; their function is to mediate the cell signaling. They are produced after some stimuli in very low amounts and just for short periods. If their concentration is higher than required, we can potentially have dangerous side effects. They could be humoral (biological fluids) or membrane (surface) mediators. Communication could be autocrine, juxtacrine/paracrine. They work thanks to specific receptors, if a cell doesn’t express it, the response will not be activated. When there is the receptor and the cytokines bind it, we have a cascade response, meaning that they can stimulate the cells to produce other cytokines causing an amplification of the response. If the response isn’t well regulated, we cannot stop the process with inhibitors. Depending on the target, the environment and the concentration, cytokines can have different biological effects such as differentiation, proliferation, cell death, and activation.

They can be:

• Pleiotropic -> One cytokine can act on different targets to produce different biological effects.
• Redundant -> More cytokines mediate for the same effect.
• Synergic -> Two or more cytokines act on a target to produce the same effect.
• Antagonist -> Two or more cytokines that have opposite effects.

Cytokines are divided into structural superfamilies (cytokines and receptors). We can classify them into pro-inflammatory or anti-inflammatory. Some can have very extreme action, others can behave and explain both functions. For example, IL-1 and TNFα are very pro-inflammatory, while IL-4, IL-10 are very anti-inflammatory, and others like TGFβ, and IL-6 can behave. The activation of the inflammation depends on the balance of cytokines. If the contact with a pathogen is not able to activate the production of this type of mediators, we will not have a response; our body will not fight the problem and that could be pathological, or maybe the pathogen/agent is not dangerous (we live in symbiosis with other organism in/on our body).

So, cytokines are very important mediators involved in the regulation of the immune-response; there is an overlap of the cells involved in the inflammation and in the a-specific immune-response. Remember: lymphocytes are activated by the presence of the antigen, not by mediators; their activation is very specific.

Cytokines could be also divided in Th1, that are pro-inflammatory, and Th2, that are anti-inflammatory (Th because they were first found to be produced in lymphocytes T helper). The Th2 cytokines are involved in the regulation of the humoral immune response and the complement system. Th1 and Th2 work in antagonism to modulate the efficiency of the response (NOT the activation). In healthy conditions, the concentration of cytokines is very low, undetectable. Cytokines are also involved in the apoptotic cell death, in particular the process is depending on their interaction with specific receptors such as FAS and TRAIL that express an intracellular death domain (extrinsic apoptotic pathway).

Mediators could be very dangerous because they can have different targets and could be involved in different kinds of diseases if not correctly regulated.

Inflammation types

Inflammation can be acute or chronic depending on the time of resolution, the infiltrate, and stromal/vascular changes.

During acute inflammation, the time of development and resolution is very fast. We have vasodilatation with an increase in permeability, meaning there is more flow of fluids (extravasation), but also that cells of inflammation can pass. Vasodilatation is caused by mediators; they act on endothelial cells, there are changing, and the tight junctions are released. Depending on the type of injury, more cells or fluids can exit. The aim is always to bring what could be useful to eliminate what is stimulating the response. Cell infiltrate is characterized by the presence of granulocytes; they can’t proliferate. The regulation is strictly regulated by humoral mediators.

During chronic inflammation, vascular changes are minimal while the stromal changes are very detectable, due to the cellular proliferation that can lead to fibrosis. The cell types involved in this response are the macrophages that can proliferate and can be persistent for a very long time (they are involved in stromal changes). The persistence of the agent could be very long.

Exudate formation

Exudate formation is provided by the inflammation process, due to the capillary change in dimension and permeability. That leads to the accumulation in the interstitial space of fluids containing salts, proteins, and leukocytes (neutrophilic).

Fluids components: protein concentration (50g/l), Ig, and fibrinogen (->fibrina). There is a high turnover rate, drained by lymphatic vessels and replacement by new exudate.

Cell components: Neutrophilic granulocytes, both from circulation and bone marrow.

Edema

Edema can be due to inflammation or not related to it but to the hydrostatic balance. Mediator can be produced both from cells or from the liver (major source). It can participate or not, and its mediators are in the plasma. All the cellular mediators activate in different phases of the inflammation. When the concentration of the mediators is very high, we can have a systemic inflammatory response -> Acute phase reaction. Ex. is fever (when the brain is involved, hypothalamus), some mediators could reach the brain.

The liver produces acute phase reaction proteins like CRP etc. One type of proteins produced in the acute phase reaction are the pentraxins, and they can also activate the complement.

Disease

7/10/2022

A disease is a condition in which the organism is facing a situation that is different from the physiological situation. It is a dynamic condition. It can cause modification in function and structure of a tissue. Can be acute or chronic. It can be localized or systemic.

The infection happens when we get in contact with a pathogen/agent, our immune system should try to fight it, resulting in the alteration of the physiological conditions. Ex. Diabetes is localized (loss of B-pancreatic cells); however, the effects are systemic.

The Erimathosis Systemic Lupus is a systemic disease in which the reaction is directed against nuclear components. This is because, in this disease, we have a high rate of apoptotic death (not release of cellular components). What happens is that the apoptotic bodies are phagocytes from macrophages, degraded, and then the antigen is presented by them to the lymphocytes. When the immune response is active, we have B-cell and T-cell, and we can detect an overproduction of antibodies against the nuclear components.

Etiology studies the causes of a disease, while pathogenesis starts from etiology, but studies the mechanisms that can lead to a disease. We know what is the cause, but the evolution could be quite different.

Focus on etiology, we can distinguish between mono-factorial or multifactorial disease. The causes could be intrinsic like for genetic disease (ex. daltonism) or extrinsic (ex. chemicals, physical, microbiological, diet related etc.). But both causes can contribute to a disease. When we don’t know what is the cause, we speak about idiopathic disease, usually they are very rare and not pursued by pharmaceutical companies.

Remember, cancer is a genetic disease that acts on somatic cells.

When something is altering the physiological conditions (homeostasis), the cells try to adapt to the new conditions. If this alteration is harder to adapt, we can go to cell injury (damage). We can distinguish between reversible and irreversible cell injuries. If it is irreversible, the cell goes to necrosis (main outcomes of inflammation) and apoptosis (components are not released in the environment). If cells can adapt, they attend a new steady state. This is a dynamic equilibrium.

When we lose the initial state, the organs try to respond to what got lost, we can have progressive (hyperplasia and hypertrophy) or regressive (hypoplasia and hypotrophy/atrophy) adaptations.

Hyperplasia

Hyperplasia is the increase in cell number and is a reversible condition (physiological/pathological hormonal stimuli, compensatory or to increase functional requirement). Generally, we can see this phenomenon in labile tissues ex. epithelial tissue, blood etc. It is balanced with the stimulus entity. The pathogenic mechanisms involve different factors such as the increasing of Growth Factors (GF) levels, but also the increasing of GF receptors and they activate different signal transduction pathways that result in cell proliferation or recruitment of stem cells and their differentiation. In case of hyperplasia, we always increase the risk of tumor development.

Ex. Hyperplasia occurs in people living at high altitude; they have more erythrocytes to compensate for the low amount of oxygen. When the stimulus is removed, the conditions return to normal. Other examples are pregnancy or liver regeneration. Liver regeneration is one of the oldest processes known; in this case, we can have two ways that can lead to regeneration. The first one is the direct hyperplasia, here we have molecules that stimulate cell proliferation; when the stimulus is removed, we return to the initial conditions. The second one is the compensatory hyperplasia, for example, when the liver is damaged by alcohol, we have a loss in the parenchyma, and cell proliferation is stimulated to restore the conditions. We need to activate the emphatic stem cells thanks to different signal transduction pathways. The peak of DNA replication occurs 24h after the damaging event, then the cells simply enlarge. There are several signals that regulate the process such as mitogens (hormones, GF, cytokines). When we need to stop the process, in the environment, we will find inhibitors and factors that stimulate the synthesis but not the proliferation.

Hypertrophy

Hypertrophy is when cells increase their volume in a physiological or pathological way; it is a reversible condition. This process can be highlighted after increasing the function ex. skeletal muscle or chronic blood overload (this is not good). The stimulation of the process can involve specific hormonal stimuli, like in pregnancy, breastfeeding, or benign prostatic hyperplasia.

We can also have pathogenic mechanisms such as mechanical stimuli, trophic stimuli (GF, vasoactive factors), enhanced protein synthesis (or reduced degradation), protein type change (in the muscle) and embryonal gene re-expression (atrial natriuretic factor).

Ex. Muscles can increase their dimensions thanks to genetic mutations -> Razza Piemontese, have a hypermuscle phenotype, due to a mutation in a gene that results in negative regulation that leads to hypertrophy. In 2004, the same mutation was detected in a child by genetic analysis.

We may have compensatory hypertrophy, evident in paired organs when there is a loss of function in one of them. Ex. in kidney, there is an enlargement of existing glomeruli (not new) and capillary elongation. The remaining kidney compensates through circulation changes. We can’t use drugs to increase muscular hypertrophy because that can also happen in other organs like in the cardiac tissue, and that would be dangerous.

The same mechanism, but opposed, can lead to hypertrophy/atrophy. This could be physiologic during development, or during restoration of normal tissue dimension.