IPF vs. PPF: Diagnostic Criteria and Pathogenesis
IPF vs PPF: the 2022 ATS/ERS diagnostic criteria (FVC ≥5% / DLCO ≥10%), AT2 senescence pathogenesis, and treatments from nintedanib to nerandomilast.
Introduction
Interstitial Lung Disease (ILD) is an umbrella term encompassing over 200 distinct disorders characterized by inflammation and/or fibrosis in the lung interstitium. Among these, Idiopathic Pulmonary Fibrosis (IPF) has historically been the most prominent and lethal.
However, recent clinical consensus recognizes that many ILDs other than IPF (such as autoimmune-related ILDs or hypersensitivity pneumonitis) can also develop a self-sustaining, irreversible "progressive fibrosing phenotype." Once this switch is flipped, the lung degrades much like it does in IPF, regardless of the original underlying disease. This broader paradigm was formally codified as Progressive Pulmonary Fibrosis (PPF) by international guidelines in 20221.
This article covers the definitions and diagnostic criteria of IPF and PPF, their molecular pathogenesis, and the treatment evolution from nintedanib to nerandomilast, grounded in the peer-reviewed literature.
1. Definitions and Diagnostic Criteria
IPF (Idiopathic Pulmonary Fibrosis)
- Definition: A specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause. It primarily affects older adults (typically men over 50). Diagnosis requires the radiological or histological hallmark pattern of Usual Interstitial Pneumonia (UIP). Serum biomarkers such as KL-6, SP-D, and MMP-7 aid in diagnosis and prognostication.
- Characteristics: By the time of diagnosis, irreversible scarring is already established. Historically, the median survival was a mere 3–5 years, proving more fatal than many common cancers.
PPF (Progressive Pulmonary Fibrosis)
- Definition: Formally codified in the 2022 ATS/ERS/JRS/ALAT clinical practice guidelines1. PPF refers to any non-IPF fibrosing ILD (e.g., Rheumatoid Arthritis–ILD, Systemic Sclerosis–ILD, chronic Hypersensitivity Pneumonitis, Non-Specific Interstitial Pneumonia, fibrotic Sarcoidosis, unclassifiable ILD) that continues to exhibit worsening despite standard appropriate management (such as immunosuppression).
- Previous Terminology: Often referred to in earlier literature as PF-ILD (Progressive Fibrosing ILD).
Formal PPF Diagnostic Criteria (ATS/ERS/JRS/ALAT 2022)
In a patient with non-IPF ILD who has radiological evidence of pulmonary fibrosis, PPF is defined by the presence of at least 2 of the following 3 criteria within the past year, with no alternative explanation1. The 2022 ATS/ERS/JRS/ALAT criteria remain the current official guideline as of 2026; a 2025 follow-up review by Kondoh and Inoue (Advances in Therapy 2025) reorganized implementation experience and terminology but kept the FVC/DLCO thresholds and the "2-of-3" rule unchanged7.
| # | Criterion | Quantitative Threshold / Specific Findings |
|---|---|---|
| 1 | Worsening respiratory symptoms | Progression of cough/dyspnea (no quantitative threshold; clinical judgment) |
| 2 | Physiological progression (PFTs) | Absolute decline in FVC ≥5% predicted or absolute decline in DLCO ≥10% predicted |
| 3 | Radiological worsening (HRCT) | Any of: increased extent/severity of traction bronchiectasis and bronchiolectasis; new ground-glass opacity with traction bronchiectasis; new reticular abnormality; new or increased honeycombing; increased lobar volume loss |
In simple terms: IPF is a disease that fibroses from day one for unknown reasons. PPF is a state where a lung, originally damaged by a known trigger, eventually enters an unstoppable, IPF-like fibrotic downward spiral.
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2. Pathogenesis: Molecular Mechanisms of Progression
While the initiating triggers for IPF and PPF differ, they eventually converge on a common final pathway of progressive, self-sustaining fibrosis.
IPF Mechanism: AT2 Cell Senescence and Aberrant Repair
The exact cause of IPF remains unknown, but the prevailing paradigm invokes "recurrent alveolar epithelial micro-injury combined with aging-related cellular dysfunction"3,4.
- Hallmarks of Aging: Aging is the single largest risk factor for IPF. Characteristic aging features — telomere attrition, DNA damage, mitochondrial dysfunction, epigenetic alterations, loss of proteostasis, and dysregulated autophagy — underpin disease biology3.
- AT2 Cell Senescence and Depletion: Alveolar Type II (AT2) cells act as stem cells for alveolar regeneration. In IPF, AT2 cells lose proliferative capacity and express cellular senescence markers, causing regeneration to fail and fibroblast-dominated aberrant repair to take over3. A 2025 review further articulates the telomere dysfunction → p53 hyperactivation → AT2 Senescence-Associated Secretory Phenotype (SASP) axis and its entanglement with mitochondrial dysfunction, positioning p53-targeted reversal of AT2 senescence as an emerging therapeutic strategy8.
- ER Stress and Apoptosis: IPF lungs show prominent endoplasmic reticulum (ER) stress in AT2 cells, leading to apoptosis — a pathological hallmark of the disease4.
- Aberrant Repair & Cytokine Surge: Instead of normal epithelial regeneration, the damaged IPF epithelium mounts an abnormal repair response, hyper-secreting profibrotic cytokines like TGF-β, FGF, and PDGF.
- Fibroblast Activation: These cytokines drive resident fibroblasts to differentiate into highly active myofibroblasts, which relentlessly secrete extracellular matrix (ECM) components such as collagen.
- Self-Perpetuation (Mechanotransduction): Stiff, scarred ECM mechanically stresses surrounding cells and activates the YAP/TAZ pathway, triggering further TGF-β release — a vicious "loop of death" independent of external triggers3,4.
- Genetic Background of Familial IPF: Familial IPF (≈5–10% of cases) is linked to mutations in telomere-related genes (TERT, TERC, RTEL1, PARN) and surfactant-related genes (SFTPC, SFTPA2). In sporadic cases, the MUC5B promoter variant (rs35705950) is the strongest common genetic risk factor3.
PPF Mechanism: Escape From Immune Control
Most diseases that lead to PPF (e.g., autoimmune ILD) initially start as classic inflammation.
- Early Stage (Inflammation-Dominant): Lymphocytes and macrophages infiltrate the lung, releasing inflammatory cytokines. At this stage, corticosteroids and immunosuppressants are highly effective.
- Failed Resolution: Normally, the M1→M2 macrophage polarization switch and SPMs (Specialized Pro-resolving Mediators: Resolvins, Protectins, Maresins) actively terminate inflammation. In PPF-prone cases, this resolution fails, allowing chronic inflammation to transition into fibrosis (Inflammation-to-fibrosis transition).
- Progression (Fibrotic Autonomy): Repeated damage over time inadvertently activates the same aberrant repair pathways seen in IPF (TGF-β release, myofibroblast activation).
- Immune Independence: Once the fibrotic cascade gains momentum, it becomes autonomous. Even if immunosuppression successfully turns off the original immune-driven inflammation, the mechanical and biochemical fibrotic loop continues. This "escape" marks PPF.
3. IPF vs. PPF at a Glance
| Feature | IPF | PPF |
|---|---|---|
| Definition | Chronic progressive UIP of unknown cause | Non-IPF ILD meeting 2022 ATS/ERS progression criteria |
| Underlying disease | None (idiopathic) | RA-ILD, SSc-ILD, chronic HP, NSIP, fibrotic sarcoidosis, unclassifiable ILD, etc. |
| Typical demographics | Older adults, male-predominant | Varies with underlying disease |
| Diagnostic anchor | UIP pattern on HRCT/biopsy | 2022 ATS/ERS criteria (2 of 3: symptoms / PFTs / HRCT) |
| Initial treatment | Anti-fibrotics as first-line | Treat underlying disease first (e.g., immunosuppression); add anti-fibrotics upon confirmed progression |
| Anti-fibrotics | Nintedanib, Pirfenidone, Nerandomilast | Nintedanib (INBUILD), Nerandomilast (FIBRONEER-ILD) |
| Prognosis | Median survival 3–5 years | Depends on underlying disease and progression rate |
4. The Evolution of Anti-Fibrotic Therapy
The realization that IPF and PPF share a common final pathogenic pathway profoundly changed the therapeutic approach.
① IPF-Exclusive Era: Pirfenidone and Nintedanib
For years, direct anti-fibrotic drugs were strictly approved only for IPF:
- Pirfenidone: Multiple actions including TGF-β pathway suppression, modulation of inflammatory cytokines, and direct inhibition of collagen fibril formation.
- Nintedanib: A tyrosine kinase inhibitor targeting PDGFR, FGFR, and VEGFR. Both slow the annual decline of FVC in IPF by approximately 50%.
② The INBUILD Trial and Expansion to PPF
"If the final fibrotic mechanism is the same, shouldn't anti-fibrotics work for any progressive fibrosing disease?" This hypothesis was proven by the landmark INBUILD trial2. Nintedanib was given to 663 patients with any non-IPF progressive fibrosing ILD. The annual FVC decline improved by 107 mL/year (placebo -187.8 mL/year vs. nintedanib -80.8 mL/year), a magnitude virtually identical to its IPF performance. Anti-fibrotic therapy thus became a standard option in PPF.
③ 2025 Update: Nerandomilast (PDE4B Inhibitor)
Nerandomilast (BI 1015550) is the first selective PDE4B inhibitor, exerting anti-fibrotic and anti-inflammatory effects via the cAMP/PKA pathway — a mechanism distinct from existing anti-fibrotics.
- FIBRONEER-IPF (Phase 3, 1,177 patients): 52-week FVC change was -183.5 mL on placebo vs. -114.7 mL in the nerandomilast 18 mg group (p<0.001)5.
- FIBRONEER-ILD (PPF Phase 3): Also met the primary endpoint; FDA granted Breakthrough Therapy Designation for PPF in April 2025.
- FDA approval: Approved as Jascayd® for IPF on October 7, 2025 (the first new IPF therapy in over a decade)9, followed by an additional approval for PPF on December 19, 2025. Can be used as monotherapy or in combination with existing anti-fibrotics; the most common adverse event is diarrhea (≈41%). Full details: IPF Treatment Landscape 2026.
④ Beyond PDE4B: LPA1 Antagonist Class
Following nerandomilast, the next mechanistic frontier is the LPA1 receptor antagonist class. The LPA1 antagonist admilparant (BMS-986278) is in Phase 3 ALOFT trials targeting both IPF and PPF, with primary completion estimated October 2026 (ALOFT-IPF, NCT06003426) and December 2027 (ALOFT-PPF, NCT06025578). Because LPA1 antagonism acts upstream of TGF-β–driven myofibroblast activation, it is a leading candidate for combination use alongside nerandomilast.
5. Implications for Preclinical Drug Discovery
Selecting animal models that reflect distinct phases of pathogenesis is crucial for IPF/PPF drug development.
Standard Model: Bleomycin-Induced Pulmonary Fibrosis
- Recommended protocol: C57BL/6 mice, intratracheal or oropharyngeal administration, both sexes evaluated, primary endpoints being hydroxyproline quantification and histology (e.g., Ashcroft score)6.
- Strengths: Acute inflammation followed by a wave of fibrosis — well-suited for evaluating anti-inflammatory/anti-fibrotic compounds and the inflammation-to-fibrosis transition seen in PPF (Bleomycin Pulmonary Fibrosis Model, optimization guide).
Limitations of the Bleomycin Model
- Fibrosis spontaneously resolves within several weeks — failing to reproduce the irreversible progression central to human IPF.
- Core IPF biology such as AT2 senescence, telomere dysfunction, and ER stress is not faithfully recapitulated.
- Many compounds successful in this model have failed in clinical trials, indicating limited predictive validity6.
Pushing Toward More IPF-Like Models
- Repeated dosing: Repetitive oropharyngeal dosing or subcutaneous mini-pump delivery to drive chronicity.
- Aged mice: Recapitulating hallmarks of aging.
- Genetically modified mice: Tert/Terc-deficient, TGF-β-overexpression lines.
- Precision-Cut Lung Slices (PCLS): Human lung ex vivo platforms.
- Clinically relevant endpoints in mice: Measuring FVC/DFCO at the preclinical stage to narrow the preclinical-to-clinical translation gap.
See the full list of pulmonary fibrosis preclinical models.
6. Conclusion
IPF (idiopathic fibrosis from day one) and PPF (fibrosis that became autonomous after prolonged inflammation) take different roads but arrive at the same destination: myofibroblast activation and runaway collagen deposition. Discovering this common pathway enabled two major advances — the expansion of anti-fibrotics (INBUILD) and a novel drug class (nerandomilast FDA approval). The next frontier lies in targeting the upstream and core of this shared pathway simultaneously: senolytics, anti-αvβ6 integrin antibodies, and mechanotransduction inhibitors, combined with better translational preclinical platforms.
References
1. Raghu G, et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022;205(9):e18-e47. PubMed
2. Flaherty KR, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases (INBUILD). N Engl J Med. 2019;381(18):1718-1727. PubMed
3. Moss BJ, Ryter SW, Rosas IO. Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis. Annu Rev Pathol. 2022;17:515-546. PubMed
4. Spagnolo P, Kropski JA, Jones MG, et al. Idiopathic pulmonary fibrosis: Disease mechanisms and drug development. Pharmacol Ther. 2021;222:107798. PubMed
5. Richeldi L, et al. Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis (FIBRONEER-IPF). N Engl J Med. 2025. PubMed
6. Jenkins RG, et al. An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis. Am J Respir Cell Mol Biol. 2017;56(5):667-679. PubMed
7. Kondoh Y, Inoue Y. Progressive Pulmonary Fibrosis: Current Status in Terminology and Future Directions. Adv Ther. 2025;42(7):2988-3001. PubMed
8. Liu S, et al. Mitochondrial dysfunction and alveolar type II epithelial cell senescence: The destroyer and rescuer of idiopathic pulmonary fibrosis. Front Cell Dev Biol. 2025;13:1535601. PubMed
9. Boehringer Ingelheim. "FDA approves JASCAYD® (nerandomilast), the first new treatment for idiopathic pulmonary fibrosis (IPF) in over a decade." October 7, 2025. BI Press Release