Fibrotic tissue in the lungs does not readily undergo normal cellular turnover due to a complex interplay of factors that fundamentally alter the tissue’s structure and cellular behavior:

• Disrupted Tissue Architecture: Fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) components, particularly collagen. This dense, stiff scar tissue disrupts the normal alveolar structure, making it difficult for cells to organize and function properly. The altered physical environment impedes the signals and interactions necessary for regular cell turnover.
• Altered Cellular Composition: In fibrotic tissue, there’s an accumulation of myofibroblasts, which are specialized fibroblasts responsible for ECM production and tissue contraction. These cells are resistant to apoptosis (programmed cell death) and contribute to the persistent fibrotic state. The balance of cell types crucial for tissue maintenance, such as alveolar epithelial cells, is also disturbed.
• Impaired Cell Signaling: The fibrotic environment is rich in pro-fibrotic growth factors and cytokines, such as transforming growth factor-beta (TGF-β). These signaling molecules promote fibroblast activation and ECM deposition while suppressing the normal processes of cell proliferation, differentiation, and apoptosis needed for tissue renewal.
• Mechanical Cues: The increased stiffness of the fibrotic tissue itself provides mechanical cues that further promote myofibroblast activity and inhibit the behavior of normal lung cells. This creates a positive feedback loop that perpetuates fibrosis and hinders normal turnover.
• Loss of Regenerative Capacity: Chronic injury and inflammation, which often precede fibrosis, can damage progenitor cells responsible for tissue repair and regeneration. In addition, aging, a significant risk factor for pulmonary fibrosis, is associated with a decline in the regenerative capacity of lung cells.
• Epigenetic Changes: Persistent fibrotic signaling can lead to epigenetic modifications in lung cells, altering gene expression patterns and promoting a stable pro-fibrotic phenotype that is resistant to reverting to normal cellular behavior.

In essence, fibrotic tissue creates a self-sustaining environment that favors the persistence of scar-producing cells and actively suppresses the normal cellular processes required for tissue repair and regeneration, including regular cell turnover. This leads to the progressive stiffening and dysfunction of the lungs characteristic of pulmonary fibrosis.

Q. Why can’t the immune system get rid of the abnormal cells in lung fibrosis, and how do antifibrotic drugs try to help?

A. The immune system’s failure to effectively clear abnormal fibrotic cells in the lungs is multifaceted:

• Evasion Mechanisms: Myofibroblasts, the primary effector cells in fibrosis, can exhibit mechanisms to evade immune surveillance and clearance. Some studies suggest they upregulate “don’t eat me” signals, similar to cancer cells, preventing phagocytosis by immune cells like macrophages.
• Skewed Immune Response: In chronic fibrotic conditions, the initial inflammatory response, which is meant to clear pathogens and initiate repair, can become dysregulated. This often involves a shift towards a T helper type 2 (Th2) biased immune response, characterized by the release of cytokines like IL-4, IL-5, and IL-13. These cytokines promote fibroblast activation and ECM production rather than clearing fibrotic cells.
• Impaired Antigen Presentation: Fibroblasts, while not traditional immune cells, can interact with the immune system. In fibrosis, their ability to present antigens appropriately to T cells for targeted destruction might be impaired.
• Physical Barrier: The dense ECM deposited in fibrotic tissue can act as a physical barrier, hindering the access of immune cells to the myofibroblasts. This makes it difficult for immune cells to directly interact with and eliminate the fibrotic cells.
• Tolerance Induction: Chronic exposure to fibrotic signals and antigens might lead to the development of immune tolerance, where the immune system becomes less reactive to these abnormal cells, failing to mount an effective clearance response.
• Senescent Fibroblasts: Senescent fibroblasts, which accumulate in fibrotic tissue, can secrete a variety of pro-inflammatory and pro-fibrotic factors (Senescence-Associated Secretory Phenotype – SASP). These factors can further dysregulate the immune response and contribute to the persistence of fibrosis.

How Antifibrotic Drugs Target These Pathways:

Current and investigational antifibrotic drugs aim to target various pathways involved in the development and progression of fibrosis, indirectly impacting the abnormal cells and the environment that sustains them. These strategies include:

• Inhibiting Pro-fibrotic Growth Factors: Many drugs target key growth factors like TGF-β and connective tissue growth factor (CTGF), which are central to fibroblast activation, differentiation into myofibroblasts, and ECM production. By blocking these signals, the drugs aim to reduce the activity and proliferation of fibrotic cells. Examples include pirfenidone (which has multiple targets including TGF-β) and monoclonal antibodies against CTGF (e.g., pamrevlumab).
• Modulating Inflammatory Pathways: Given the link between chronic inflammation and fibrosis, some antifibrotic drugs target inflammatory cytokines and signaling pathways. For instance, nintedanib inhibits multiple tyrosine kinases, including those involved in growth factor signaling and potentially influencing inflammatory responses. Newer drugs like preferential phosphodiesterase 4B (PDE4B) inhibitors (e.g., BI 1015550) aim to reduce pro-inflammatory cytokine release.
• Targeting ECM Production and Remodeling: Some approaches focus on inhibiting the enzymes involved in ECM synthesis or promoting its degradation. For example, drugs targeting lysyl oxidase-like 2 (LOXL2), an enzyme involved in collagen cross-linking, are being investigated.
• Interfering with Fibroblast Activation and Differentiation: Several drugs in development aim to block the differentiation of fibroblasts into myofibroblasts or to promote their apoptosis. This can involve targeting specific integrins (e.g., αvβ6) that activate TGF-β or other signaling pathways involved in myofibroblast formation.
• Modulating Immune Cell Activity: While not directly targeting fibrotic cells for clearance by the immune system, some experimental therapies explore ways to re-educate the immune system or dampen pro-fibrotic immune responses. This might involve targeting specific cytokines or immune cell populations. For example, some research explores the potential of immunotherapies to reactivate immune surveillance against fibrotic cells by blocking “don’t eat me” signals like CD47.
• Targeting Mechanotransduction: Recognizing the role of tissue stiffness in perpetuating fibrosis, some strategies aim to interfere with the mechanical signaling pathways that activate myofibroblasts.

It’s important to note that currently approved antifibrotic drugs primarily focus on slowing disease progression rather than reversing fibrosis or directly eliminating the abnormal cells. Future therapies may involve more targeted approaches to modulate the immune system and promote the clearance of fibrotic tissue.

Q. Are scientists working on any stem cell treatments to grow healthy lung cells again? And is there anything in the works to actually get rid of lung scars?

A. You’re asking about two very exciting and actively researched areas in lung disease: stem cell replacement therapy and scar elimination. Here’s the current landscape:

Stem Cell Replacement Therapy in the Lung:

The idea of using stem cells to regenerate healthy lung tissue and replace damaged cells is a promising avenue of research, but it’s not yet a standard clinical treatment for most lung diseases, including pulmonary fibrosis. However, there’s significant ongoing work in this area:

• Types of Stem Cells Being Studied: Researchers are investigating various types of stem cells for lung repair, including:
  • Mesenchymal Stem Cells (MSCs): These are the most widely studied due to their anti-inflammatory and tissue-regenerative properties. They can be sourced from bone marrow, adipose tissue, umbilical cord tissue, and other sources.
  • Induced Pluripotent Stem Cells (iPSCs): These are adult cells reprogrammed to an embryonic-like state, capable of differentiating into various cell types, including lung cells. This approach bypasses ethical concerns associated with embryonic stem cells and can potentially use a patient’s own cells, reducing the risk of immune rejection.
  • Lung-resident Progenitor Cells: The lungs themselves contain progenitor cells that can regenerate damaged tissue. Research is focused on understanding how to stimulate these endogenous cells.
• Approaches and Research:
  • Cell Transplantation: Studies are exploring the direct delivery of stem cells (usually MSCs) into the lungs via intravenous infusion or bronchoscopy. The goal is for these cells to engraft, differentiate into healthy lung cells, and secrete factors that promote repair and reduce inflammation.
  • Decellularization and Recellularization: This involves stripping a donor lung (or even an animal lung) of all its cells, leaving behind a scaffold of the lung’s structure. This scaffold is then “reseeded” with stem cells derived from the patient, with the aim of growing a new, functional lung for transplantation. This is currently in the very early research stages.
  • Stimulating Endogenous Repair: Research is also looking at using small molecules or other therapies to activate the lung’s own resident stem and progenitor cells to repair damage.
• Current Status and Challenges:
  • Most stem cell therapies for lung diseases are currently in preclinical studies (animal models) or early-phase clinical trials (Phase I and limited Phase II) primarily focused on safety and feasibility.
  • While some early trials have shown signals of potential benefit in terms of slowing disease progression or improving quality of life, no large-scale, randomized, controlled trials have yet demonstrated definitive efficacy for stem cell therapy in conditions like pulmonary fibrosis.
  • Challenges remain in ensuring effective engraftment and differentiation of transplanted cells, controlling their behavior to prevent unwanted side effects, and understanding the optimal cell type, dosage, and delivery method.
  • The American Lung Association and other medical societies currently advise patients to only consider stem cell therapy for lung diseases within the context of approved clinical trials due to the lack of proven benefit and potential for harm from unproven therapies offered outside of this framework.

Research in Eliminating Scars (Fibrosis):

Reversing established scar tissue in the lungs is a major goal of research in pulmonary fibrosis and other fibrotic lung diseases. Current antifibrotic drugs primarily aim to slow down the progression of scarring, not eliminate existing scars. However, there’s growing excitement about potential therapies that could achieve this:

• Targeting Key Fibrotic Pathways: As we discussed earlier, researchers are investigating various molecules and pathways that drive fibrosis. New therapies aim to:
  • Inhibit Pro-fibrotic Cytokines: Blocking key drivers like TGF-β and IL-11 has shown promise in preclinical studies for not only reducing but potentially reversing fibrosis.
  • Modulating ECM Production and Degradation: Targeting enzymes involved in collagen production (like LOXL2) or enhancing the activity of enzymes that break down ECM is under investigation.
  • Interfering with Myofibroblast Activity: Strategies to promote myofibroblast apoptosis or revert them to a less active fibroblast state are being explored.
  • Targeting Mechanotransduction: Blocking the signaling pathways that respond to tissue stiffness could help to “soften” the fibrotic tissue and reduce the signals that perpetuate fibrosis.
• Emerging Therapeutic Targets: Recent research has identified novel targets that show potential for reversing lung scarring in preclinical models:
  • Focal Adhesion Kinase (FAK) Inhibitors: Some studies have shown that inhibiting FAK can lead to a significant reduction in lung fibrosis in animal models and even in human lung tissue samples.
  • YAP/TAZ Inhibitors: Blocking these proteins in immune cells has shown promise in reducing lung scarring and promoting regeneration in preclinical models.
  • HIF-2 Inhibitors: Targeting this signaling pathway in abnormal lung epithelial cells has shown potential to promote alveolar repair and limit fibrosis.
  • S100A4 Inhibitors: Inhibiting this protein has reversed lung stiffness in preclinical models.
  • MicroRNA Modulation: Targeting specific microRNAs, like miR-33, in immune cells has demonstrated the ability to reverse lung scarring in mice.
  • Barasertib (AURKB Inhibitor): This drug, initially studied for cancer, has shown the ability to reverse fibroblast activation and reduce scar tissue in mice with lung fibrosis.
• Current Status and Future Directions:
  • Many of these promising scar-reversing therapies are currently in preclinical development.
  • Some have moved into early-phase clinical trials to assess safety and initial signs of efficacy in humans.
  • The development of effective scar-reversing therapies is a complex process, and it will take time to determine if these approaches are safe and effective in patients with pulmonary fibrosis and other fibrotic lung diseases.
  • Combination therapies that target multiple pathways may ultimately be necessary to achieve significant scar reversal.

In summary, while stem cell replacement therapy holds great promise for the future of lung disease treatment, it is not yet a standard therapy. Similarly, research into eliminating lung scars is rapidly advancing, with several promising targets and therapies in preclinical and early clinical development. The next few years are likely to bring significant progress in both of these exciting fields.