A Brief Independent Study on Idiopathic Pulmonary Fibrosis Cell Therapeutic Regeneration

Abstract:

Idiopathic Pulmonary Fibrosis(IPF), a hidden killer, is an enigma that has posed thousands of questions that yield almost no answers. IPF leaves behind a complicated problem set many have worked on for years. It is a rare but acute disease that needs a cure, meaning a viable and successful treatment/cure is imperative for the well-being of current and future generations. With thousands of people working on finding treatments that slow the progression of the illness, what is next? How or when will a cure be found? Can a cure even be found for idiopathic diseases? How are idiopathic diseases like IPF even detected? These questions have prompted my independent study. This paper will serve as a recorded recollection of what I've learned through researching potential cures for IPF and contacting leaders in the field. Recent developments have suggested promise in cell regeneration; therefore, I'll discuss recent studies showing promise for lung cell regeneration. Moreover, I'll delve into the application of IPF therapy and its effectiveness in slowing the disease's progression or curing it.

Introduction:

What is Idiopathic Pulmonary Fibrosis(IPF)? IPF is when the alveoli in the lungs become damaged or scarred. It is most recognizable when breathing becomes difficult; one has continuing dry coughs, excessive tiredness, a loss of appetite, and swollen fingertips. Idiopathic Pulmonary Fibrosis mainly manifests itself in people between the ages of seventy to seventy-five(1). Although treatments exist, they only slow the progression; nothing as of today exists to reverse the scarring. In turn, causing the lungs to become stiff, ultimately making it difficult for oxygen to get into the bloodstream. The reason IPF exists is unknown; however, recent studies have linked the disease to exposure to dust: wood and metal, viral infections, chronic smoking, and family history. One in twenty people with IPF has a family member with the same condition (1). Although leading scientists in the field can link IPF to specific occurrences, a particular cause has yet to be discovered. In infected lungs, normal lung cells are replaced by destructive alveolar cells and permanently change the extracellular matrix(2). This change to the extracellular matrix causes a difference in the gas exchange process, leading to the slow demolition of the lungs. As the lung decreases in function, many patients with the symptoms mentioned above will visit their pathologist to undergo a series of tests to detect any lung abnormalities.

Detection:

With a disease so adverse and rare, how is IPF detected among people? Pathologists follow a series of five detection points and methods: blood tests, breathing tests, chest x-rays, CT scans, and a bronchoscopy.

1. Blood Tests: Should there be trepidation regarding lung abnormalities, a pathologist will conduct a blood test. The test would measure how adequately the lungs transfer oxygen into your bloodstream. This first test will not provide the complete picture; however, it is a good streamline into first noticing any discrepancies in normal lung function.

2. Breathing Tests: Secondly, a pathologist will conduct a breathing test, otherwise referred to as a pulmonary function test. The test records the function of the lungs. It measures how much the lungs can physically hold and how quickly you can breathe. A spirometer is used to conduct this test; spirometry is when a doctor instructs their patient to breathe into a mouthpiece that's remotely attached to a monitor. A pathologist will then compare the test results to the results of a healthy breathing rate of someone of the same caliber(3).

3. Chest X-Rays: The next step in the process would be to get a scheduled chest x-ray. The X-ray will not show the lungs pictured in detail; however, the images can help doctors spot more considerable and more apparent discrepancies

4.  CT Scan: Following a chest x-ray, a CT scan of the patient will be run, ultimately providing doctors with more finely-detailed images.

5. Bronchoscopy: Doctors will resort to a bronchoscopy after conducting the tests mentioned above. A bronchoscopy is a narrow flexible tube with an attached camera( bronchoscope) inserted through the mouth and passed down through the airways. A small piece of the lung tissue is then taken from the patient and later examined for abnormalities.

IPF's rarity is so severe that doctors often misunderstand and misdiagnose it. An actual IPF diagnosis is reached in two of every three IPF patients(6). This diagnosis is most commonly found by using a CT scan. The difference between IPF and other lung diseases is that it's chronic and will only progress through the lung, meaning that someone with IPF will never fully recover.

Potential Cures:

Although treatments are helpful and essential in medicine, finding a cure is imperative for chronic illnesses like IPF. Treatments are a viable option, but with IPF's high mortality rate: 64.3 deaths per million in men and 58.4 deaths per million in women(7) and its financial burden, a cure would be exponentially advantageous. It's necessary to discover the root problem of the disease and reverse scarring to the lungs rather than slowing its progression.

How can a cure for an idiopathic disease be found? Although researchers and analysts haven't seen the direct cause of IPF, they know precisely what IPF targets and how the lung slowly scars. They know how lung scarring occurs, but they don't understand why. How does IPF scarring occur? Enzymes are a primary reason for the expanding progression of fibrosis in the lungs. The RNA telomerase activity changes depending on the cell; the progression will ultimately affect the lung stem length. Telomerase will attach itself to the RNA strand and add complementary base pairs. Although this is normal telomerase function, telomerase activity in fibrosis-infected lungs will develop anti-apoptotic qualities, meaning that the cells will continue growing without undergoing proper cell death. With that information, a new idea has been introduced: cell-based therapy. Stem cells are the main form of cell-based therapy, which includes alveolar and lung epithelial cells. The main focal point of cell-based regeneration is replacing damaged(scarred) cells with regenerated cells. A few different kinds of cells can be used to replace damaged(scarred) cells.

What kind of cells can be used to replace the damaged ones? So far, cell-based therapy research is at the forefront for the cure of IPF, but what kinds of cells are used? How many different types of cells are currently being tested? So far, Alveolar Epithelial Cells( AECs), Mesenchymal Stem Cells(MSCs), Embryonic Stem Cells(ESCs), and Lung Stem Cells. According to Ahmed H K El-Hashash and Qi Lu's research study, the most promising is the Alveolar Epithelial Cells( AECs).

1. Alveolar Epithelial Cells Alveolar Epithelial Cells, when freshly isolated, have shown promising results with the tion of collagen contents; thus, Alveolar Epithelial can potentially heal many lung injuries. In addition, recent studies demonstrate that alveolar Epithelial Cells may help to inhibit the progression of scarring in the lungs and aren’t harmful to the human participants of the trial. As seen in Table 1 and Table 2:

2. Mixed Lung Epithelial Cells Mixing lung epithelial cells can quickly and efficiently allow cell-based therapy(9). In addition, the delivery of lung epithelial cells into a BLM animal model has improved lung fibrosis (9)

3. Stem Cells Stem cells have been a “go to” proposal when dealing with chronic and idiopathic diseases, which is why they are so promising for inhibiting the spread of IPF in the lung. Stem cells have two distinct properties: complete regeneration and differentiation. Stem cells from the umbilical cord and bone marrow can handle idiopathic diseases like IPF.

   1. Mesenchymal Stem Cells(MSCs): Adult MSCs, derived from adult bone marrow, can be differentiated to occupy a wide range of niches, meaning they can occupy many different cell lines (15). Furthermore, they target damaged cells and tissues through intraperitoneal(IP) and intravenous(IV) injections. Thus, MSCs can inhibit the progression of lung scarring through their anti-apoptotic quality. A summary of the clinical study exploring the applicability of MSCs to chronic diseases is shown in Table 3.

   2. Placental MSCs: These cells come from the umbilical cord or aborted fetuses and have high stem cell counts. Based on the study results, they have been found to inhibit the progression of scarring in the lung and are anti-inflammatory

   3. Bone Marrow MSCs: Bone Marrow MSCs are the most common form of MSCs and have been the prime kind of stem cell used in IPF research. In addition, the granulocyte colony-stimulating factor(G-CSF) has improved lung scarring in clinical trials; therefore, the Bone Marrow MSCs play a pivotal role in healing different scarring sites in the lung for pulmonary fibrosis victims.

   4. Adipose tissue-derived mesenchymal stem cells (ADSCs) : These cells can act as an alternate form of stem cells. They can be extracted through liposuction and yield bioactive factors, including the HGF, a hepatocyte growth factor. ADSCs can also drastically improve the repeating intra-tracheal implementation of BLM(24). In a study focusing on the effects of using ADSCs as a treatment for IPF, it was shown that ADSCs could be used to monitor different cells that result in the flaring of lung tissue scarring. Table 5 summarizes the result of the study.
      

ADMINISTRATING CURES

Although cell-based therapies are promising, finding a way to administer said cures is a significant challenge. However, through multiple trials, there have been three potentials for the administering problem: intravenous(28), intratracheal(21), and intraperitoneal(29) installations; each route plays a crucial role in the success of cell-based cures for IPF.

TREATMENTS

What is the difference between a treatment and a cure? Treatment is defined as a drug or a procedure that can improve someone's health or aid them in their recovery from an injury. A cure is a drug, procedure, or therapy that will restore a patient's health. There are no current cures for IPF, meaning that fibrosis in the lungs can only be slowed down with the treatments available. The Food and Drug Administration (FDA) has approved two treatments for IPF: Pirfenidone and Nintedanib.

1. Pirfenidone: Aims to slow down the progression of scarring in the lung tissues. It accomplishes this goal by reducing the activity of the body's immune system. Pirfenidone comes in capsule form and is taken three times a day. Pathologists only recommend this treatment for those whose pulmonary function test is fifty to eighty percent less than it should be. If the scarring in the lung progresses even when taking medicine, it is typically stopped.

2.  Nintedanib: Whereas Pirfenidone is an older and more popular treatment, Nintedanib is a newly developed treatment aiming to slow down the scarring progression in the lungs. Like Pirfenidone, Ninetanib is taken in capsule form; however, unlike Pirfenidone, Ninetanib is only taken twice a day. Like with Pirfenidone, doctors only recommend this treatment for those whose pulmonary function test is fifty to eighty percent less than it should be. If the scarring in the lung progresses even when taking medicine, it is typically stopped.

A transplant is the only cure for this disease; however, it’s highly uncommon and not feasible.

1. Lung Transplantation: A lung transplantation is a viable and successful cure for IPF patients whose symptoms are limited. The problem with this, however, is that getting a donor whose lung is a match for the patient in question is very rare. Therefore, although a lung transplant is viable and will eliminate scarring, obtaining such a transplant is very selective.

PROPER DOSE

Not only is the route of a cell-based therapy important, but the number of cells reaching the target site is also essential. The smallest amount of cells necessary to generate significantly beneficial and safe outcomes, which varies among research, is the most effective cell dosage for successful cell treatment. Therefore, numerous attempts have been made to objectively assess the effectiveness and safety of various dosages of MSCs and other kinds of stem cells.

CURRENT TRIALS

Although there is no viable treatment for IPF, there are some encouraging in vitro and preclinical studies. Human disorders like IPF that use stem cell-based therapies are typically still in the early experimental stages and lack established clinical procedures. There are still several active clinical trials for the stem cell-based treatment of IPF (3,28). The effectiveness, safety, and tolerability of cell-based therapeutics in humans are the primary goals of these clinical studies. Teratoma risk (tumor development), hazards linked to cell handling techniques and culture/storage protocols, and additional risks connected to surgical procedures, immunosuppression, comorbidities, and allergic immunological reactions, are all part of the risk profile in these trials. Stem cells employed in these clinical trials may be at a high risk of developing tumors since they are prospective candidates for malignant transformation. An illustration of the possible danger of tumor development in transplanted stem cells in people is a patient who got transplanted stem cells and acquired a donor-derived multifocal brain tumor four years after transplantation (18). The effectiveness of stem cell therapy methods is one of the main goals of ongoing clinical trials. Several critical issues need to be resolved to assess the efficacy of a stem cell-based therapeutic approach. These include choosing the best delivery method to effectively recruit stem cells to the lung and the best technique to induce the functional differentiation of recruited stem cells into lung epithelium to achieve successful therapeutic effects. Successful cell-based therapy can result from effectively addressing these issues, including the optimal dose and timing for delivery. Due to their low immunogenicity, the minimal danger of developing teratomas, and the absence of possible ethical issues, MSCs are the most often employed stem cells in contemporary clinical studies (20,22). MSCs produced from the human placenta and BM are particularly common in IPF clinical studies (26,28). The majority of IPF clinical trials, however, are still in Phase I and II and have not yet been finished.

CONCLUSION

BMSC transplantation successfully restores patients' damaged blood systems (20), and skin-derived stem cells used to treat patients with severe burns are two of the few cell-based treatments employed in clinics (21). These cell-based therapies also include cord blood stem cells employed for hereditary blood illnesses like children's Fanconi anemia and malignant blood disorders like leukemia (20). Interestingly, cell-based treatment may effectively treat a range of chronic human ailments. However, while efforts are being made to identify safer and more effective cell treatment techniques, many problems still need to be solved.

Genetic polymorphism of specific genes is linked to developing IPF susceptibility (23-24). Consequently, combining gene therapy with cell-based treatment may provide a fresh approach to treating IPF. Creating genetically altered stem cells utilizing viral vectors that target IPF illness has been proposed (17). Compared to other lung conditions, lung fibrosis, such as cystic fibrosis, is a suitable target for gene therapy because of the simplicity of lung access and the cloning and characterization of the CFTR gene (25). However, this type of therapy still has many obstacles and difficulties (25).

Utilizing the cytokine's impact on the targeted cells to enhance cell-based treatment is another promising approach. This will primarily be based on our comprehension of the operational functions of cytokines and signaling molecules in boosting the effectiveness of immune cells and cells responsible for mending the injured lung, which is widely explored (26). Implementing Cell Therapeutic Regeneration is consequently crucial for the effective cell-based therapeutic method. This study serves as a written reminder of what I have discovered while looking for IPF treatments and speaking with experts in the field. I presented new research that showed potential for lung cell regeneration in the light of recent breakthroughs in cell regeneration. I have also studied how IPF therapy is used and how well it works to stop the progression of the illness or even cure it.

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