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In IPF & PPF,

WHEN EPITHELIAL
DEFENSES FALL,
PROGRESSION FOLLOWS.1,2

 

Repeated epithelial injury and faulty repair initiate IPF and PPF—yet this upstream mechanism remains incompletely addressed. Understanding where the disease begins could reshape how we approach progression.1,3

 

Epithelial injury: A repeated assault in IPF and PPF

Epithelial cells are the lungs’ first line of defense and are undergoing recurrent injury and faulty repair in IPF and PPF.1-3


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A driver of fibrogenesis not yet directly targeted: Faulty epithelial repair

Current therapies do not directly address all three key drivers of fibrogenesis, particularly faulty epithelial repair, which is a central upstream contributor.3,4

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The LPA1 pathway: A promising target

 

LPA₁ is implicated across all three key drivers of fibrogenesis and is an important focus of research in IPF and PPF.5,6


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Epithelial injury:
A repeated assault in IPF and PPF1-3

The course of disease is shaped by repeated epithelial injury 

Over time, repeated epithelial injury may overwhelm the lungs’ first line of defense, disrupting normal repair processes. A growing body of research suggests that cycles of epithelial damage and faulty repair contribute to the progression of IPF and PPF.1-3



Disease progression is variable and unpredictable

IPF and PPF do not follow a consistent pattern. Recurrent epithelial injury occurs sporadically across lung tissue, contributing to patchy fibrosis observed on imaging. As a result, progression can vary significantly from patient to patient. Patients face potentially irreversible loss of lung function when lung architecture is disrupted in IPF and PPF.7-10

 

Epithelial cell injury and faulty repair are the start of a damaging cascade in IPF and PPF1,3,11



A driver of fibrogenesis not yet directly targeted: Faulty epithelial repair3,4

IPF and PPF are not driven by a single dysfunctional pathway2,12

When healthy lungs experience tissue injury, the wound healing response in epithelial cells is appropriately activated. In IPF and PPF, an abnormal repair response results in accumulating tissue damage.3

Faulty epithelial repair, inflammation mediated by vascular leakage, and fibroblast expansion/activation are the three key drivers of fibrogenesis.13,14

Today’s therapies do not directly target all three key drivers that shape fibrogenesis and particularly what initiates the cascade—faulty epithelial repair.3,4


Three key drivers of fibrogenesis driving the disease

Driver 1: Faulty epithelial repair

Faulty repair following recurrent epithelial injury results in cell membrane breakage that initiates the damage in IPF and PPF.1,3

Driver 2: Inflammation

Inflammation mediated by vascular leakage can lead to architectural changes in the lungs.15


Driver 3: Fibroblast expansion

Fibroblast expansion leads to excessive collagen deposition and contributes to irreversible loss of lung function.12,16


Emerging science is enhancing our understanding about how LPA1 plays a role in IPF and PPF5



The LPA1 pathway:
A promising target5,6

The LPA1 pathway is a promising target that impacts the three key drivers of fibrogenesis

Current research is focusing on the role of the LPA1 pathway in impeding normal epithelial cell regeneration and in facilitating enhanced vascular permeability and increased fibroblast recruitment. Understanding this role may provide insight into how IPF and PPF progress and potential ways to manage the disease.5,6

The LPA1 pathway has a role in all three key drivers of fibrogenesis

Driver 1: Faulty epithelial repair

The LPA1 pathway impedes normal epithelial cell regeneration after repeated injury.17

Driver 2: Inflammation

The LPA1 pathway leads to enhanced vascular permeability.13

 

Driver 3: Fibroblast expansion

The LPA1 pathway increases fibroblast recruitment to sites of damage.13

 Watch the video to see what happens when LPA1 is activated

 

Bristol Myers Squibb is researching the LPA1 pathway and its involvement across the three key drivers of fibrogenesis—and its potential in the treatment of IPF and PPF.5,6

IPF=idiopathic pulmonary fibrosis; LPA1=lysophosphatidic acid receptor 1; PPF=progressive pulmonary fibrosis.


References
  1. Mei Q, Liu Z, Zuo H, Yang Z, Qu J. Idiopathic pulmonary fibrosis: an update on pathogenesis. Front Pharmacol. 2022;12:797292.
  2. Kang HK, Song JW. Progressive pulmonary fibrosis: where are we now? Tuberc Respir Dis (Seoul). 2024;87(2):123-133.
  3. Wang J, Chao J. Epithelial cell dysfunction in pulmonary fibrosis: mechanisms, interactions, and emerging therapeutic targets. Pharmaceuticals (Basel). 2025;18(6):812.
  4. Lizé M, Mayr CH, Bleck M, et al. Targeting the epithelium in pulmonary fibrosis. Eur Respir Rev. 2026;35(179):250225.
  5. Volkmann ER, Denton CP, Kolb M, et al. Lysophosphatidic acid receptor 1 inhibition: a potential treatment target for pulmonary fibrosis. Eur Respir Rev. 2024;33(172):240015.
  6. Shea SS, Tager AM. Role of the lysophospholipid mediators lysophosphatidic acid and sphingosine 1-phosphate in lung fibrosis. Proc Am Thorac Soc. 2012;9(3):102-110.
  7. Quinn C, Wisse A, Manns ST. Clinical course and management of idiopathic pulmonary fibrosis. Multidiscip Respir Med. 2019;14:35.
  8. Podolanczuk AJ, Thomson CC, Remy-Jardin M, et al. Idiopathic pulmonary fibrosis: state of the art for 2023. Eur Respir J. 2023;61(4):2200957.
  9. Diaz CM, Caballeria E, Torres JS. Comparative analysis of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis: epidemiology, pathophysiology, clinical features, diagnosis and treatment. Fibrosis. 2025;3(1):10001.
  10. Raghu G, Remy-Jardin M, Richeldi L, 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).
  11. Yu QY, Tang XX. Irreversibility of pulmonary fibrosis. Aging Dis. 2022;13(1):73-86.
  12. Spagnolo P, Kropski JA, Jones MG, et al. Idiopathic pulmonary fibrosis: disease mechanisms and drug development. Pharmacol Ther. 2021;222:107798.
  13. Tager AM, LaCamera P, Shea BS, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med. 2008;14(1):45-54.
  14. Cui D, Che X, An R, et al. Current understanding of pulmonary fibrosis: pathogenesis, diagnosis, and therapeutic approaches. Can Respir J. 2025;2025:3183241.
  15. Probst CK, Montesi SB, Medoff BD, Shea BS, Knipe RS. Vascular permeability in the fibrotic lung. Eur Respir J. 2020;56(1):1900100.
  16. Ma H, Liu S, Li S, Xia Y. Targeting growth factor and cytokine pathways to treat idiopathic pulmonary fibrosis. Front Pharmacol. 2022;13:918771.
  17. Funke M, Zhao Z, Xu Y, Chun J, Tager AM. The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury. Am J Respir Cell Mol Biol. 2012;46(3):355-364.
References