Key Mechanisms of Fibrogenesis in Pulmonary Fibrosis

Rachel Knipe: Hello, I’m Rachel Knipe, a pulmonologist specializing in interstitial lung disease (ILD), with a clinical focus on the diagnosis and management of pulmonary fibrosis.

Lida Hariri: And I’m Lida Hariri, a pathologist and physician scientist whose work centers on the histopathology and mechanistic drivers of fibrotic lung disease.

Rachel Knipe: In this video series, we will discuss the continuum of fibrogenesis in pulmonary fibrosis and how this biology applies to both idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). Despite heterogeneous initiating triggers, the disease largely converges on shared downstream mechanisms that can sustain progressive fibrosis. 

Lida Hariri: IPF and PPF are progressive, irreversible, and often fatal fibrotic lung diseases, highlighting the importance of understanding and characterizing these mechanisms. Let’s begin! 

Rachel Knipe: ILDs are a diverse group of parenchymal chronic restrictive disorders featuring inflammation and/or fibrosis of the lung interstitium. Pulmonary fibrosis (PF) represents a subset of these conditions characterized by progressive scarring of the lung tissue, which, if progressive, can lead to irreversible loss of lung function.

Lida Hariri: Despite differences in etiology and clinical presentation across ILD subtypes, fibrotic ILDs largely converge on shared downstream mechanisms of injury, aberrant repair, and self-perpetuating fibrosis. In the following chapter, we will explore the two primary fibrotic phenotypes discussed in this series: idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF).

Rachel Knipe: IPF is a very specific type of chronic, progressive, fibrosing ILD with no identifiable cause. It is irreversible and can progress to respiratory failure and death. IPF is diagnosed by the presence of radiologic or histologic features of usual interstitial pneumonia (or UIP) and progressive worsening of both dyspnea and lung function in the absence of an identifiable cause of disease. PPF is characterized by radiologic evidence of pulmonary fibrosis, together with at least 2 of the following occurring within the past year and with no alternative explanation: worsening respiratory symptoms, physiologic progression, or radiologic progression of the fibrosis. 

Lida Hariri: In PF, recurrent epithelial injury leads to an aberrant wound healing response that triggers downstream fibrotic remodeling. The later fibrotic phase is shared across IPF and PPF, with commonalities in fibroblast activation and differentiation driving established fibrosis. Once established, structural tissue changes and a profibrotic milieu form a feed-forward loop that can perpetuate the fibrosis. 

Rachel Knipe: Periodic pulmonary function testing is the most frequently used measure for monitoring the course of pulmonary fibrosis and the response to therapy. 

Lida Hariri: The clinical reality is that no serum biomarker has been validated and clinically implemented for monitoring disease progression or for distinguishing inflammatory from fibrotic components in pulmonary fibrosis. Mechanistic models that explain how progression can become self-sustaining and why shared downstream pathways matter across ILDs are useful to better understand disease pathogenesis. 

Rachel Knipe: The response to lung injury typically involves coordinated biological processes that restore structure and function. 

Lida Hariri: When dysregulated, wound-healing responses result in excessive scar formation characterized by the accumulation of fibroblasts, myofibroblasts, and extracellular matrix. 

Rachel Knipe: Increased numbers of apoptotic cells have been observed in both alveolar and bronchial epithelia in IPF. Epithelial apoptosis is considered relevant to fibrogenesis because injured alveolar epithelial cells release cytokines and growth factors that promote fibroblast recruitment, activation, and myofibroblast differentiation. This supports the idea that persistent epithelial injury can shift repair toward maladaptive remodeling. In the shared-phase model of fibrotic ILDs, repeated epithelial injury and faulty epithelial cell repair are described as early pathogenic events that can contribute to progressive fibrosis in IPF and in PPF. 

Lida Hariri: Vascular leak following tissue injury and increased alveolar-capillary permeability are key contributors to the progression of pulmonary fibrosis. Increased permeability promotes extravasation of coagulation proteins into the airspaces, where they can be activated and contribute to profibrotic processes. 

Rachel Knipe: Fibroblast recruitment and activation at sites of injury represent central events in the development of lung fibrosis. Activated fibroblasts are cells that synthesize collagen and other extracellular matrix components that distort lung architecture.

Lida Hariri: In the late phase of the fibrotic cycle, fibroblast activation and extracellular matrix production lead to lung remodeling and microscopic honeycombing. This feed-forward biology helps explain why progressive fibrosis can persist even when the trigger is no longer present or dominant. 

Rachel Knipe: Bronchoalveolar lavage fluid from patients with IPF has demonstrated potent chemoattractant activity for fibroblasts, and this activity correlated with disease severity and progression. Biochemical characterization revealed that this chemoattractant activity is associated with a lipid fraction bound to albumin, and the active mediator was subsequently identified as lysophosphatidic acid (LPA). 

Lida Hariri: LPA is a bioactive lysophospholipid that signals through specific G protein–coupled receptors, including LPA1. LPA regulates cell migration, survival, proliferation, contraction, and gene expression in multiple cell types, all of which are relevant to wound-healing responses. This positions LPA–LPA1 signaling as a key axis that can influence injury responses. 

Rachel Knipe: LPA-LPA1 signaling perpetuates fibrogenesis in the lung by driving three key processes: epithelial injury, vascular leakage, and fibroblast activation and expansion. Let’s look at the evidence behind each. As we've discussed, increased epithelial cell apoptosis in response to injury is now recognized as playing a central role in pulmonary fibrogenesis. Emerging evidence indicates that LPA–LPA1 signaling directly contributes to this process.

Lida Hariri: Mice deficient in LPA1 show significantly fewer apoptotic cells in both the alveolar and bronchial epithelium early after bleomycin-induced lung injury compared with wild-type mice, suggesting that LPA–LPA1 signaling promotes epithelial apoptosis after injury. Consistent with these in vivo findings, LPA signaling through LPA1 has also been shown to induce apoptosis in cultured human bronchial epithelial cells and in a rat alveolar epithelial cell line. 

Rachel Knipe: Together, these findings identify epithelial apoptosis as a core mechanistic driver — alongside vascular leak and fibroblast recruitment — through which LPA–LPA1 signaling can perpetuate fibrogenesis after lung injury. In mouse models following bleomycin-induced lung injury, LPA levels increased in bronchoalveolar lavage fluid, linking injury to increased LPA availability in vivo. Mice deficient in LPA1 receptors demonstrate reduced vascular leak and are protected from lung fibrosis and mortality following bleomycin-induced lung injury. These findings support a mechanistic role for LPA1 signaling in the response to lung injury and development of fibrosis in vivo.

Lida Hariri: In patients with IPF, LPA levels are reported to be increased in bronchoalveolar lavage samples compared with controls. Among the LPA receptor subtypes, LPA1 is expressed at high levels on fibroblasts recovered from IPF bronchoalveolar lavage fluid, identifying it as the primary receptor mediating fibroblast responses to LPA in this disease context. Inhibition of the LPA1 receptor markedly reduced fibroblast chemotactic responses in IPF bronchoalveolar lavage fluid. These findings link the LPA pathway to fibroblast recruitment in human fibrotic lung disease. 

Rachel Knipe: LPA has been implicated in lung fibrosis because it has been shown to regulate epithelial apoptosis, vascular permeability, fibroblast migration, and profibrotic mediator activation. LPA–LPA1 signaling is reported to contribute to epithelial apoptosis after lung injury based on evidence from knockout mice and cultured epithelial cell cultures. LPA can disrupt endothelial barrier function in vitro through signaling pathways that promote cytoskeletal rearrangements and paracellular gap formation. Reduced vascular leak and reduced intra-alveolar coagulation are observed in LPA1 knockout mice after bleomycin-induced lung injury, providing a pathway-level link between LPA1 signaling and injury-associated profibrotic processes. 

Lida Hariri: LPA is a potent inducer of the migration of multiple cell types, including fibroblasts, and LPA–LPA1 signaling is suggested as predominantly responsible for fibroblast recruitment in the bleomycin model. LPA–LPA1 signaling is also reported to promote fibroblast persistence by suppressing fibroblast apoptosis. This dual role in fibroblast recruitment and survival represents a distinct profibrotic mechanism by which LPA–LPA1 signaling may drive progressive fibrosis. The profibrotic role of LPA–LPA1 signaling is not limited to the lung. In experimental models, LPA1 deficiency attenuates fibrosis in the peritoneum, kidney, liver, and skin, establishing LPA1 as a mediator of organ-level fibrosis across multiple tissue compartments. Taken together, these mechanisms position LPA signaling as relevant across the continuum from injury through fibrogenesis. 

Lida Hariri: The key takeaway is that progressive fibrosing lung disease reflects a continuum from injury and faulty epithelial repair to self-perpetuating fibrosis that can occur in both IPF and in PPF. 

Rachel Knipe: Within that continuum, understanding shared downstream pathways is critical for characterizing and assessing disease progression. Thank you for watching.

Ahluwalia N, Shea BS, Tager AM. Aberrant wound healing and fibrogenesis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2014;190(8):867-878. 

Kolb M, Vázquez C, Crestani B, Maher TM. Phosphodiesterase 4B inhibition: a potential novel strategy for treating pulmonary fibrosis. Eur Respir J. 2023;32:220206. 

Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-440. 

Ma H, Liu S, Li S, Xia Y. Molecular classification of idiopathic pulmonary fibrosis: personalized medicine, genetics and biomarkers. Front Pharmacol. 2022;13:918771. doi:10.3389/fphar.2022.918771

Maher TM, Stowasser S, Voss F, et al. Forced vital capacity decline and mortality risk in fibrosing interstitial lung disease. Respirology. 2023;28(12):1147-1153. 

Mei Q, Liu Z, Zuo H, Yang Z, Qu J. Idiopathic pulmonary fibrosis: an update on pathogenesis. Front Pharmacol. 2022;12:797292. doi:10.3389/fphar.2021.797292

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):e18-e47. 

Sakai N, Chun J, Duffield JS, Wada T, Bhatt DL, Tager AM. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. FASEB J. 2013;27(5):1830-1846.

Sakai N, Chun J, Duffield JS, et al. Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor. Kidney Int. 2017;89(5):1093-1107.

Samarelli AV, Tonelli R, Heijink I, et al. Dissecting the role of mesenchymal stem cells in idiopathic pulmonary fibrosis: cause or solution. Front Pharmacol. 2021;12:692551. doi:10.3389/fphar.2021.692551 

Selman M, Pardo A. When things go wrong: exploring possible mechanisms driving the progressive fibrosis phenotype in interstitial lung diseases. Eur Respir J. 2021;58:2004507. 

Shea BS, 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. 

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. 

Volkmann ER, Denton CP, Kolb M, et al. LPA1 signaling and fibrogenesis in pulmonary fibrosis. Eur Respir Rev. 2024;33:240015. 

Wijsenbeek M, Cottin V. Spectrum of fibrotic lung diseases. N Engl J Med. 2020;383(10):958-968.