pathopys- week 18/19 IPF

TGF-1

TGF-1 plays a central role in lung fibrosis by mediating profibrotic responses, which require the cooperative action of PDGF and ErbB receptor tyrosine kinases.

Nintedanib

Nintedanib is a tyrosine kinase inhibitor that blocks pathways mediated by PDGF, FGF, and VEGF, reducing fibroblast proliferation and activity.

Dual therapy with Pirfenidone and Nintedanib

The potential benefits and toxicity issues of using both Pirfenidone and Nintedanib in a dual-therapy regimen for IPF are still under evaluation.

Expected outcome of IPF drug treatment in the first two years

IPF drug treatments are expected to slow disease progression and improve Forced Vital Capacity during the first two years of treatment.

Epithelial-Mesenchymal Transition (EMT)

EMT contributes to fibrosis by recruiting fibroblasts from various sources and promoting excessive ECM deposition in response to lung injury.

Role of fibroblasts in the progression of IPF

Activated fibroblasts transition to myofibroblasts, releasing excessive ECM and contributing to increased tissue stiffness and self-sustaining fibrosis.

CCL2 in IPF

CCL2 is a chemokine that attracts immune cells, including fibrocytes, to the lungs, contributing to the fibrotic process in IPF.

Relationship between TGF-1 and CTGF in IPF

TGF-1 mediates its profibrotic effects partly through the production of CTGF, which plays a significant role in fibrosis.

Primary pharmacotherapeutics approved for IPF

Nintedanib and Pirfenidone are the primary drugs approved for IPF, targeting various profibrotic pathways.

Mechanism of action of Pirfenidone

Pirfenidone inhibits several pathways implicated in fibrosis, including TGF, FGF, and PDGF signaling, thus reducing fibrosis progression.

Bleomycin-induced IPF model

The Bleomycin model mimics pulmonary toxicity through oxidative stress, allowing researchers to study inflammatory and fibrotic responses in the lungs.

Significance of MMP2 and TIMP2 in IPF

The balance between MMP2 and TIMP2 is crucial in regulating ECM turnover, with imbalances contributing to fibrosis.

Limitations of IPF drug treatments according to clinical trials

IPF drug treatments do not improve all-cause mortality, with no significant difference observed between treated and untreated patients.

Challenges of using animal models in IPF research

The multifactorial nature of IPF and the unclear pathogenesis complicate the development and application of appropriate preclinical animal models.

Key processes inhibited by Nintedanib in fibrosis

Nintedanib inhibits fibroblast proliferation, motility, TGF-induced differentiation to myofibroblasts, and ECM deposition.

Gross pathology observed in IPF via chest CT imaging

CT imaging shows predominantly lower lobe, peripheral, subpleural fibrotic lesions with honeycombing, characterized by multiple cysts filled with air.

Mechanism of fibrosis in IPF

Fibrosis in IPF results from chronic inflammation and an aberrant wound healing response, leading to excessive extracellular matrix deposition and scar tissue formation.

Common risk factors for developing IPF

Risk factors include viral infections, smoking, pollution, genetic predisposition, and gastroesophageal reflux disease (GERD).

Epithelial-Mesenchymal Transition (EMT) in IPF

EMT is a process where epithelial cells transform into mesenchymal cells, contributing to fibrosis and tissue repair in response to injury or inflammation.

Matrix metalloproteinases (MMPs) in IPF

MMPs are enzymes that degrade extracellular matrix components and are upregulated in IPF, promoting inflammation and fibrosis.

Two main cell types in the alveolar epithelium

The two main cell types are alveolar type I (ATI) cells, which facilitate gas exchange, and alveolar type II (ATII) cells, which produce surfactant.

Effect of aging on the incidence of IPF

The effect of aging on the incidence of IPF is not explicitly defined in the notes.

IPF

A chronic, progressive lung disease characterized by unknown cause, scarring of lung tissue, and poor prognosis with a median survival of 3-5 years.

Early detection and treatment of IPF

Early detection and treatment can improve survival rates in patients with IPF.

Fibrocytes

Fibrocytes, derived from bone marrow, contribute to lung pathology by producing ECM components and participating in fibrotic processes.

Alveolar type I (ATI) cells

ATI cells cover 90% of the airway surface and are primarily responsible for gas exchange.

MUC5B

MUC5B is a mucin associated with genetic predisposition in IPF, where its overproduction can lead to airway obstruction and impaired mucociliary clearance.

Platelet-derived growth factor (PDGF)

PDGF enhances vascular permeability and recruits leukocytes to the injury site, contributing to inflammation and fibrosis.

Mucociliary clearance (MCC)

MCC relies on a gel-like mucus layer, primarily composed of MUC5B, to trap and remove inhaled particles and microbes from the lungs.

Surfactant

Surfactant reduces surface tension within the alveoli, preventing collapse and facilitating gas exchange.

Mucin overproduction in obstructive airway diseases

Mucin overproduction in obstructive airway diseases, such as IPF, collapses the periciliary layer, impairing mucociliary clearance.

Honeycombing in IPF

Honeycombing on imaging is indicative of advanced fibrosis and is associated with poor prognosis in IPF.

Alveolar type II (ATII) cells

ATII cells synthesize and secrete surfactant proteins and extracellular matrix components, crucial for maintaining alveolar space and reducing surface tension.

Digital clubbing

Digital clubbing is associated with reduced oxygen levels in the blood and characterized by softening nail beds and enlarged fingertips.

Inflammatory mediators and fibrosis in IPF

Inflammatory mediators trigger fibroblast activation, leading to the secretion of pro-fibrotic cytokines and excessive extracellular matrix production.

Myofibroblasts in IPF

Myofibroblasts, derived from fibroblasts, play a key role in wound healing but contribute to excessive ECM accumulation and fibrosis in IPF.

Genetic variants like MUC5B rs35705950

The MUC5B rs35705950 variant is associated with increased MUC5B expression in IPF lungs and influences survival and response to treatment.

Cell death in the alveolar epithelium in IPF

The primary cause of cell death in the alveolar epithelium in IPF is recurrent injury and inflammation, leading to impaired gas exchange.

Aberrant wound healing in IPF

Aberrant wound healing in IPF refers to an imbalanced repair process that leads to excessive fibrosis instead of normal tissue regeneration.

Gastroesophageal reflux disease (GERD) and IPF

GERD is a risk factor for IPF, potentially exacerbating lung damage through aspiration and inflammation.

Extracellular matrix (ECM) in lung tissue

ECM provides structural support for lung tissues, regulates cell behavior, and is crucial for tissue repair and remodeling.

Alveolar epithelium and gas exchange

The alveolar epithelium, consisting mainly of ATI cells, is structured to facilitate efficient gas exchange between the air and blood.

Chronic inflammation and IPF

Chronic inflammation leads to repeated injury, fibroblast activation, and ultimately excessive scar tissue formation in the lungs.

TGF-β in IPF

TGF-β is a key pro-fibrotic cytokine that mediates fibroblast activation and ECM deposition in the lungs.

Impaired gas exchange in IPF

Impaired gas exchange in IPF results in reduced oxygen levels in the blood, leading to symptoms like dyspnea and digital clubbing.