General Pathology: Introduction, Cellular Adaptation and Degeneration

Introduction and Program

Textbooks: Robbins and Cotrans, Pathologic basis of disease. Rubin's pathology: Clinicopathologic foundations of medicine Exam: Oral General Pathology is a very important subject because it studies the causes and mechanisms of diseases. It is also important for the creation of the therapy which is the mechanism, origin, and molecular biology of human disease.

Program of the Course

First of all, it is important to understand which are the main causes of diseases:

• Infectious disease: General principles of microbial pathogenesis, viral infections bacterial infections, fungal infections, parasitic infections
• Environmental pathology: effect of temperature and radiations

After studying the main causes of diseases, there are also other important topics of general pathology such as cellular pathology.

After any kind of damage, the cell tries to reestablish its homeostasis (for example if there is denaturation of a protein, the cell will try to repair the protein; if there is DNA damage the cell will try to repair it and it will stop its cell cycle to prevent the transmission of DNA damage). The reestablishment of the original homeostasis is achieved through the cellular stress response. However, the cell does not always succeed in this response so after cellular stress, if there is a failure in this response, the cell must adapt to the new situation.

Another important topic of general pathology is cellular adaptation.

• Cellular adaptation: in this response, cells can enlarge their volume (become hypertrophic) or they can diminish their volume (become hypotrophic). In some cases, there is a modification of the phenotype of the cell (Metaplasia). It is important to understand that In some cases these cellular adaptations are physiologic, however, in some cases, they can be pathologic (for example when there is hypertension we have pathologic hypertrophy of the heart that can lead to heart failure.
• Cellular degeneration:

1. Steatosis: cells accumulate lipids, in particular, triacylglycerols; this type of damage can occur for example in the liver.
2. Hydrophobic degeneration: we have an accumulation of water inside the cell due to the failure of the Na/K pump after the depletion of ATP.
3. Vacuolar degeneration: the cell will accumulate vacuoles in the cytosol due to an alteration of the plasma membrane permeability.
4. Enlargement of mitochondria: mitochondria are very important for the cell because they can produce, through the oxidative phosphorylation, a large amount of ATP; if there is an alteration of mitochondria, we have a decreased production of ATP, the subsequent depletion of it, and the blocking of the Na/K pump.

• Cell death: 3 types of cell death mechanisms can be classified according to the morphology of dead cells.

1. Necrosis: Some cells before dying are larger; they will accumulate water inside (Oncosis) and more importantly there will be the disruption of the plasma membrane of the cell with the exit of the cytosol.
2. Apoptosis: The cell is smaller than normal, there is the release of bodies from the cell. This type of cell death is characterized by the presence of an intact plasma membrane.
3. Autophagy: it consists in the digestion of particles or subcellular organelles of the cell.

• Inflammation: it is the first response of our organism after damage. If there is the release of cytosol from the cell after necrosis, immediately there is the activation of inflammation; phagocytes will arrive at the site of damage and engulf the necrotic cell or eventually a pathogen. Through phagocytosis, inflammation tries to remove the damage. Inflammation can be acute or chronic and these two types have completely different pathogenic mechanisms.

1. Chronic inflammation: there is an infiltration of lymphocytes in the tissue without having an important involvement of the vessels; the main involvement is of monocytes that become macrophages.
2. Acute inflammation: there is an important involvement of the vessels, for this reason, acute inflammation is called angiophlogosis; we also have the involvement of neutrophils.

• Thermoregulation: the aim of inflammation is to perform phagocytosis to remove the pathogen; however, this mechanism is local (phagocytosis can be performed in the tissue), but inflammation is a systemic event and this is due to the release of pro-inflammatory cytokines. Pro-inflammatory cytokines can induce systemic effects of inflammation, they can modify the temperature set point in the hypothalamus, so pro-inflammatory cytokines are responsible for the appearance of a fever (an increase of body temperature).
• Tissue repair: after inflammation and phagocytosis, damages in the tissue result anyway, so the next step for the body is tissue repair. There are different modalities of tissue repair.

1. Regeneration: there are tissues made by cells that can proliferate after a given stimulus, so these types of tissue can undergo regeneration. Healing is achieved by cell proliferation and also by remodeling of the extracellular matrix.
2. Fibrosis: there are tissues made up of cells not able to proliferate (cardiomyocytes and neurons for example cannot proliferate). For this reason, when there is damage and death of these cells ( called permanent cells) the only way to repair the tissue is to add an extracellular matrix which will lead to fibrosis.

• Neoplasia: Unfortunately, tumors are caused by chemical, viral, physical, and biological agents. These agents can alter genes involved in cellular proliferation. We have 2 classes of genes involved in cellular proliferation:

1. Protooncogenes: they are able to positively affect cellular proliferation and, when there is DNA damage, in these genes there is a gain of functions so that protooncogenes become oncogenes (genes that induce an increase of cellular proliferation and affect cellular transformation).
2. Oncosuppressor genes: they are able to inhibit cell growth. Unfortunately, during cellular transformation, we have a loss of function of oncosuppressor genes and these genes cannot counteract anymore the activity of protooncogenes. Also, oncosuppressor genes can induce DNA repair.
• Tumor classification: it is important to understand the difference between benign and malignant tumors. It is important to know the classification according to the nomenclature of these tumors (for example adenoma and adenocarcinoma) or between a tumor arising from the epithelium or mesenchymal tissue. It is important to know the different behavior between benign and malignant tumors. A benign tumor cannot metastasize while a malignant can. The problem in the prognosis of cancer patients is the fact that malignant tumors can invade other tissues and grow in these tissues, thus the prognosis can be very serious.
• Chemical carcinogenesis: they are represented, for example, by several compounds present in food; they are also represented by products in the environment that can induce alterations in DNA.
• Viral agents induce cellular transformation: serval viruses can induce cellular transformation. Examples are RNA viruses, but the majority are DNA viruses. Just one class of retrovirus can induce cancer in humans, which is the HTLV1 that can induce Humans T- cell leukemia. Also, viral proteins produced after the infection can induce cellular transformation.
• Some elements of pathophysiology: we are going to talk about Atherosclerosis because it is very important and it causes several complications and then we are going to talk about thrombosis.
• Technical science of Laboratory medicine: (prof. Fabiani)

Etiology and Pathogenesis of Disease

General pathology studies the etiology, so the cause of diseases, and the pathogenesis of a disease which are the mechanism by which a disease is caused. Pathogenesis is very important because it can lead to alteration in the structure and function of a given tissue and eventually can lead to disease.

It is also important for a given disease to understand the why and where of signs and symptoms for employing a therapy for this disease.

Disease: it is a condition in which a normal function, structure, tissue, and organ is altered. To have a disease you need to react to the organism.

Disease Phenomena and Injury Location

To summarize we need 2 phenomena: first alteration of an organ and then the response of the organism.

It is very important to define the type of injury the type of reaction of the organisms and then the location of the injury.

For this reason, it is important to categorize different diseases; you would expect that an agent (chemical, physical and biological) would induce direct damage on the cell. Sometimes an agent can induce indirect damage: for example, the activity of ionizing radiations can damage directly the DNA, proteins, and lipids. Indirect damage due to the interaction of ionizing radiations with water leads to the production of reactive oxygen species, which can induce damage to the cell. Also, when there is the activity of the carbon tetrachloride poisoning, we have indirect damage which is due to the production of trichlormethylperoxide which is a free radical and induce alteration in lipids, proteins, and DNA. So, some diseases are caused not by a direct activity of a given compound or radiation but are due to the indirect effect of that given compound.

In other cases, we can have several causes that can act simultaneously, for example, we can have a hemodynamic injury in the endothelium in the heart, and then we can have the presence of the microorganism in the blood. This can lead to infective thrombi to the heart valve surface and the co-presence can cause endocarditis. So, in this case, we have 2 components acting together, on one side we have the hemodynamic injury and on the other side, we have the presence of bacteria and together induce the damage.

Theories to Categorize a Disease

Carbon Tetrachloride Poisoning

A Carbon tetrachloride poisoning Free radical release Liver cell necrosis Liver ER The carbon tetrachloride induces free radical release in the endoplasmic reticulum (ER) of the liver cells and this leads to lipid peroxidation and liver cell necrosis

Infective Endocarditis

B Infective endocarditis Haemodynamic Injury Endothelium in heart Bacteraemia Thrombosis Haemodinamic injury to the endothelium within the heart (scarred mitralic or aortic valve) will in the presence of microrganisms in the blood, give rise to infected thrombi on the heart valve surface (endocarditis).

We also have to see the disease from a different point of view.

Direct relationship: We may have when there is damage, a lesion that causes the loss or alteration of a function. The cell is not able to repair the damage, there is a structural change in the cell and then we have the appearance of symptoms and signs.