BPA2101 Medical Pathology Answer

Introduction Of BPA2101 Medical Pathology Answer 

Question 1: Cause and Mechanism of cell injury and cell death

Cell injury can be defined by the sequence of events that occur when the stresses exceed the ability of cells to adapt. On the other hand, cell death is caused when continuing injury becomes irreversible, and the cell cannot recover. Cell injury occurs when the cells are exposed to harmful stressors and stimuli that disrupt normal cell function. The most common cause of cell injury includes physical trauma, exposure to chemical agents, microbes or foreign pathogens, and nutritional imbalance. The mechanism of cell injury includes oxidative stress which causes radical damage to cell membrane and organelles, and dysfunction of mitochondria which leads to depletion of ATP and calcium influx (Guo et al., 2013). Cell injury can be caused in two ways: Necrosis and apoptosis. On the other hand, cell death can be triggered by various causes including physical damage, oxygen depletion in cells (hypoxia), deprivation of nutrients, exposure to toxins or genetic mutation. The two primary mechanisms of cell death are necrosis and apoptosis (Miller & Zachary, 2017). Necrosis is a pathological process which causes acute cell injury and uncontrolled cell death. The external factors that stimulate the necrosis are ischemia, infection, exposure to toxins, and trauma which cause rapid cell damage (Khalid & Azimpouran, 2023). On the other hand, apoptosis is a regulated and programmed process of cell death and is essential to maintain cellular homeostasis (National Human Genome Research Institute, 2023). Apoptosis includes two major pathways- intrinsic (mitochondria) and extrinsic (death receptor-mediated) pathways.

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(Figure: Mechanism of Apoptosis)

Question 2: Apoptosis and necrosis, difference and similarities

Apoptosis and necrosis are two distinct mechanisms of cell death, which differ from each other in terms of mechanisms, triggers, and outcomes.

Differences:

1. Mechanism: Apoptosis is a regulated and energy-dependent process which initiated by extrinsic and/or intrinsic signals. In apoptosis, the intrinsic pathway is triggered by internal stress signals like oxidative stress, damage of DNA or oncogene activation, and key mediators are Bcl-2 proteins and proapoptotic proteins like Bax, and Bak which induce the release of cytochrome-c (National Human Genome Research Institute, 2023). On the other hand, the extrinsic pathway of apoptotic cell death is initiated by the binding of death ligands to death receptors (Fas, TNFR), and key mediators are receptor-ligand interaction recruits adaptor proteins like FADD, and procaspase-8, and Caspase-8 (Jan & Chaudhry, 2019). In contrast, necrosis is the unregulated mechanism of cell injury which triggered by ischemia and toxin and causes ATP depletion, loss of ion homeostasis, membrane rupture, and release of intracellular content which further causes inflammation.
2. Mitochondrial role: In the case of apoptosis, mitochondria play an important role, starting from the release of cytochrome c, activating caspase-9, and the apoptosome. In the case of necrosis, mitochondrial dysfunction causes the failure of ATP production and activates the necrotic signalling pathway (Khalid & Azimpouran, 2023).
3. Inflammatory response: Apoptosis is a non-inflammatory mechanism, whereas necrosis causes cell inflammation, lysis and release of damage-associated molecular patterns (DAMPS) that trigger the inflammation.

Similarity: both apoptosis and necrosis initiate from the cellular stress of injury, and include calcium dysregulation and mitochondrial dysfunction.

Question 3: Relevance of necrosis and apoptosis in normal and disease state

In normal state:

Apoptosis is an important mechanism for normal cell development and maintaining cellular homeostasis. It regulates cell turnover and provides shapes to the tissues during embryogenesis. This mechanism is also important for maintaining immune balance by eliminating the dysfunctional cells and ensuring maintaining proper size of organs and functions. Apoptosis is also important for suppressing the accumulation of oncogenic cells by eliminating the DAN damage mechanism (Jan & Chaudhry, 2019). On the other hand, necrosis used to be absent in normal cell conditions, and it is not involved in regular cell turnover.

In disease state:

Necrosis in the disease state plays an important role due to its nature of causing cell death through rupture of the plasma membrane and release of damage-associated molecular patterns or DAMPs protein. In the case of inflammatory diseases, like multiple sclerosis and rheumatoid arthritis, necrosis triggers the release of DAMPs and causes cellular inflammation and tissue damage. On the other hand, during ischemic injuries, necrosis occurs due to a lack of blood supply and it causes tissue damage and inflammation (Jog & Caricchio, 2014). Necrosis is also relevant for neurodegenerative diseases like Alzheimer’s disease where it causes neuronal loss and disease progression.

In the case of apoptosis, it can be stated that cell death contributes to tissue homeostasis by balancing the mitosis. The caspase-dependent apoptosis can be characterised by the activation of pathways that cause the release of proteases and result in the disruption of cells without leakage of cellular components (Favaloro et al., 2012). In the case of cancer, alteration of apoptosis plays an important role in cancer development and defects in apoptotic pathways can cause resistance to the therapy.

Discuss the processes of acute and chronic inflammation. What are the key cellular and molecular mechanisms involved, and how do these processes influence disease progression and drug therapy?

Discussion on acute and chronic inflammation

Acute inflammation refers to the body’s immediate response to injury, or harmful stimuli, such as infection or tissue damage (Hannoodee & Nasuruddin, 2021). It is a short-term process that lasts from a few hours to a few days. Chronic inflammation refers to slow, long-term inflammation that lasts several months to years. The extent and effect of chronic inflammation vary with the cause of the injury and the ability of the body to repair and overcome the damage (Pahwa et al., 2019).

Mechanism of acute inflammation including timelines, cells involved, mediators, and effects

Acute inflammation initiates with specific cell injuries, which trigger the release of soluble mediators like cytokines, acute phase proteins, and chemokines. It is an immediate and adaptive response with limited specificity and is caused by noxious stimuli like infection and tissue damage. The mediators of acute inflammation are exogenous inducers which include pathogen-associated molecular patterns, and virulence factors like exotoxin. On the other hand, endogenous inducers of acute inflammation included damaged and stressed tissues. Apart from that the major mediators of acute inflammation are histamine, which causes vasodilation, prostaglandins and bradykinin and Cytokines like IL-1 and TNF-α (Hannoodee & Nasuruddin, 2021). The cells which are involved in acute inflammation are neutrophils (early responders), macrophages (late-stage repair), mast cells and endothelial cells which trigger the release of mediators. Considering the timeline, immediate response occurs for acute inflammation in 0-1 hours which includes vascular changes, vasodilation, and increased permeability with cell swelling. The early phase lasts from 1 to 24 hours whereas the late phase starts from 24 hours to 48 hours when the macrophages replace the neutrophils, clean the cell debris and initiate cell repair. The possible outcomes of acute inflammation include the formation of abscesses, fibrosis formation, recruitment of immune cells and pathogen destruction.

(Figure: Mechanism of acute inflammation)

Mechanism of chronic inflammation, including timelines, cells involved, mediators, and effects/outcomes

Chronic inflammation refers to slow, long-term inflammation which lasts for a prolonged period of several months to years. The cells involved in chronic inflammation are macrophages which contribute to the initiation, regulation, and resolution of inflammation; innate lymphoid cells or ILCs which contribute to chronic inflammation and autoimmune disease, mast cells which are the key components of the inflammatory process, eosinophils, and myeloid-derived suppressor cells (dendritic cells, immature macrophages, granulocytes cells) (Pahwa et al., 2019). The key mediators involved in chronic inflammation are mononuclear cells, growth factors including TGF-β, EGF, b-FGF, vascular endothelial growth factors or VEGF; MDSCs or myeloid-derived suppressors cells, and inflammatory mediators like cytokines, arachidonic acid. Nitric oxide, and oxygen-free radicles (Abdulkhaleq et al., 2018). The probable outcomes of chronic inflammation include destruction of tissue from persistent immune activity, fibrosis or scarring due to excessive collagen deposition, and granuloma formation in response to persistent infections like tuberculosis.

(Figure: Mechanism of Chronic Inflammation)

2 disease states and briefly discuss how the inflammation process influences the progression

1. Cancer: chronic inflammation can be linked to the development and progression of cancer. The key mechanism includes the release of cytokines, where chronic inflammation in oncogenic cells triggers the release of pro-inflammatory cytokines including IL-1 and TNF-α, which can further activate the oncogenic pathway and inhibit the tumour suppressor genes (Zhao et al., 2021). Inflammation in the case of cancer can contribute to the development of TME pr tumor microenvironment which can allow the tumors to evade immune detection and destruction.
2. Rheumatoid arthritis or RA: in the case of RA, chronic inflammation causes activation of the synovial membrane, which results in the recruitment of lymphocytes, and macrophages. In this disease, the cell inflammation triggers the release of pro-inflammatory cytokines like TNF-α, and IL-1 which can damage the cartilage and cause bone erosion (Heo et al., 2024).

Discussion on 2 drugs that could be used to target the inflammation process

1. Cancer: IL-1 and TNF-α inhibitors- drugs like anakinra an IL-1 receptor antagonist can be employed to suppress the pro-inflammatory effects of cytokines in TME or tumour microenvironment. By blocking the IL-1 signalling, anakinra can reduce the proliferation of tumour cells, which in turn can reduce cellular resistance to cancer therapies (Hübner et al., 2020). Additionally, adalimumab another anti-TNF-α monoclonal antibody can inhibit the TNF-α activity and reverse the immune evasion mechanism.
2. Rheumatoid arthritis: in the case of RA, targeting the pro-inflammatory cytokines is important to manage the symptoms and prevent joint damage. Etanercept and infliximab are the anti-TNF-α proteins that bind to the TNF-α receptor and prevent inflammation, along with diminishing lymphocyte and macrophage recruitment (Patel & Wadhwa, 2021). This in turn decreases the rate of cartilage degradation and bone erosion and improves the patient outcome.

References

• Abdulkhaleq, L. A., Assi, M. A., Abdullah, R., Zamri-Saad, M., Taufiq-Yap, Y. H., & Hezmee, M. N. M. (2018). The Crucial Roles of Inflammatory Mediators in inflammation: a Review. Veterinary World, 11(5), 627–635. https://doi.org/10.14202/vetworld.2018.627-635
• Favaloro, B., Allocati, N., Graziano, V., Di Ilio, C., & De Laurenzi, V. (2012). Role of Apoptosis in disease. Aging (Albany NY), 4(5), 330–349. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384434/
• Guo, C., Sun, L., Chen, X., & Zhang, D. (2013). Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regeneration Research, 8(21), 2003–2014. https://doi.org/10.3969/j.issn.1673-5374.2013.21.009
• Hannoodee, S., & Nasuruddin, D. N. (2021, November 21). Acute Inflammatory Response. PubMed; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK556083/
• Heo, J., Heo, S., Joo Ri Kang, Kweon, J., Lee, Y., & Baek, J.-H. (2024). Rheumatoid arthritis: a complex tale of autoimmune hypersensitivity. Exploration of Immunology, 358–375. https://doi.org/10.37349/ei.2024.00146
• Hübner, M., Effinger, D., Wu, T., Strauß, G., Pogoda, K., Kreth, F.-W., & Kreth, S. (2020). The IL-1 Antagonist Anakinra Attenuates Glioblastoma Aggressiveness by Dampening Tumor-Associated Inflammation. Cancers, 12(2), 433. https://doi.org/10.3390/cancers12020433
• Jan, R., & Chaudhry, G.-S. (2019). Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics. Advanced Pharmaceutical Bulletin, 9(2), 205–218. https://doi.org/10.15171/apb.2019.024
• Jog, N. R., & Caricchio, R. (2014). The role of necrotic cell death in the pathogenesis of immune mediated nephropathies. Clinical Immunology, 153(2), 243–253. https://doi.org/10.1016/j.clim.2014.05.002
• Khalid, N., & Azimpouran, M. (2023, March 6). Necrosis. PubMed; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK557627/
• Miller, M. A., & Zachary, J. F. (2017). Mechanisms and Morphology of Cellular Injury, Adaptation, and Death. Pathologic Basis of Veterinary Disease, 2-43.e19. https://doi.org/10.1016/b978-0-323-35775-3.00001-1
• National Human Genome Research Institute. (2023). Apoptosis. Genome.gov. https://www.genome.gov/genetics-glossary/apoptosis#:~:text=Apoptosis%20is%20the%20process%20of
• Pahwa, R., Jialal, I., & Goyal, A. (2019, June 4). Chronic Inflammation. NIH.gov; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK493173/
• Patel, S., & Wadhwa, M. (2021). Therapeutic use of specific tumour necrosis factor inhibitors in inflammatory diseases including COVID-19. Biomedicine & Pharmacotherapy, 111785. https://doi.org/10.1016/j.biopha.2021.111785
• Zhao, H., Wu, L., Yan, G., Chen, Y., Zhou, M., Wu, Y., & Li, Y. (2021). Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduction and Targeted Therapy, 6(1). https://doi.org/10.1038/s41392-021-00658-5

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