Fibroblast embedded in extracellular matrix
Computer generated illustration of a fibroblast embedded within the extracellular matrix (ECM). The ECM consists of a network of macromolecules such as collagen, enzymes, and glycoproteins. Credit; Getty Images

Idiopathic pulmonary fibrosis (IPF) is typically characterized by lung remodeling and the pathological deposition of extracellular matrix (ECM). How exactly this works remains a mystery—hence the word “idiopathic” in the name of this disease. 

However, scientists are getting closer to a framework for understanding the pathophysiology of this disease. For one, it is a condition that primarily affects older adults, which suggests aging might have something to do with the onset of this disease: mitochondrial dysfunction, oxidative stress, and cell senescence. 

Siekacz led a team of researchers to compose a study on the interaction between the mitochondria and the ECM in the development of IPF, which was recently published in Oxidative Medicine and Cellular Longevity. The main theory of note in their work is the premise that mitochondrial dysfunction influences the composition of ECM, and vice versa. Could cross-talk between the mitochondria and the ECM be primarily responsible for the ECM changes in IPF? We will explore this question and more in this article. 

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Pathological ECM Development  

One of the most accepted hypotheses regarding IPF pathophysiology is that it is caused by multiple long-term microinjuries to the lung that eventually lead to alveolar epithelial dysfunction. However, an expanded view of this theory would include the role of the mitochondria. This is because the mitochondria are involved in multiple important cellular functions besides cellular respiration. For example, they are heavily involved in the processes of aging that might make normal lung healing more difficult, such as genomic instability, shortened telomeres, oxidative injury, and more. 

Read more about IPF etiology 

Another commonly accepted hypothesis regarding IPF pathophysiology is that antioxidant reduction and an increase in reactive oxygen species initiates inflammation, triggers the processes of aging, and disorganizes the ECM. In this hypothesis, the mitochondria once again play center stage.

“Mitochondrial alterations are associated with aging. Moreover, mitochondrial impairment increases gradually with age,” Siekacz et al commented. “Indeed, lung cells of patients with IPF are more prone to cellular stress related to mitochondrial dysfunction and consequently, fibrosis.”

Let’s look at why pathological ECM expansion presents such a major problem in IPF. The main cells that drive excessive ECM protein are myofibroblasts. The overstimulation of platelet-derived growth factors, fibroblast growth factors, and epithelial growth factors help drive this process forward. Then, ECM expansion quickly decreases the population of the alveolar epithelial cells. This results in less space for normal gaseous exchanges to occur in the lungs. 

Siekacz et al presented an expanded list of the potential roles of the mitochondria in the pathophysiology of IPF: “Numerous aspects of mitochondrial pathology including biogenesis dysfunction, fission-fusion equilibrium, mitophagy impairment, or mitochondrial reactive oxygen species overproduction seem to play a role in the pathobiology of lung fibrosis.” 

The crucial point here is that a deeper understanding of the role that the mitochondria play in IPF pathogenesis could guide future treatment research. Progress would mean moving the involvement of mitochondria in IPF from the realm of hypothesis to premise. As Siekacz and colleagues boldly predict, “Further research on mitochondrial functioning in IPF may potentially lead to a deeper understanding of its pathobiology and aid in elaborating new therapeutic approaches, which can ameliorate prognoses.” 

The IPF Cell Atlas 

Neumark et al have come up with a fascinating idea to help researchers and physicians conduct future studies on the IPF ECM: the creation of their IPF Cell Atlas. They noted that recent developments in single-cell RNA sequencing (scRNAseq) have opened the door for researchers to interrogate tissues at cell-level resolution.

“This technology allows researchers to closely examine every single individual cell within a sequenced sample to identify their cell types, functions, and ultimately the molecular signatures and cellular interactions guiding their function within the context of that tissue and human disease,” they explained. “With such breadth and depth, scRNAseq is a powerful tool that is particularly appealing to better untangle the intricate multicellular complexity of the human IPF lung.” 

Read more about IPF patient education 

With the goal of making IPF scRNAseq data accessible to all, the research team has created the IPF Cell Atlas, an easy-to-use dissemination portal.

“Within the context of single-cell work on IPF, we sought to minimize these barriers by creating an easy-to-navigate web interface that provides researchers public access to the four major single-cell IPF datasets mentioned above with several standardized visualization tools for independent differential gene expression analysis,” they wrote.

“Any scientist, regardless of their computational skill or physical location, can easily access this website for independent data mining of the datasets and novel expression pattern exploration,” they added.

There is a common thread running through the work of both teams referenced in this article: the ambitious desire to untangle the mysteries of IPF pathophysiology by proposing new theories and harnessing all available tools to conduct high-quality research that can potentially change the IPF treatment landscape. Knowing that pathological ECM formation is part and parcel of IPF is but a starting point. What we do with that information, and how we process it, may demonstrate the way forward in IPF research for the decades to come. 


Siekacz K, Piotrowski WJ, Iwański MA, Górski P, Białas AJ. The role of interaction between mitochondria and the extracellular matrix in the development of idiopathic pulmonary fibrosis. Oxid Med Cell Longev. Published online October 18, 2021. doi:0.1155/2021/9932442

Neumark N, Cosme C Jr, Rose KA, Kaminski N. The Idiopathic Pulmonary Fibrosis Cell Atlas. Am J Physiol Lung Cell Mol Physiol. 2020;319(6):L887-L893. doi:10.1152/ajplung.00451.2020