Much has been written about the pathophysiology of idiopathic pulmonary fibrosis (IPF). In this article, we will be looking specifically at the processes that drive fibrosis, and how scientists think it occurs.
To understand how fibrosis of the lungs occurs in IPF, we first need to understand how proper wound healing takes place in a normal individual. This is because lung fibrosis is a direct result of an aberrant wound healing process.
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“Once epithelial cell injury has occurred, the lung, like other organs, repairs itself through the process of wound healing,” Moss and colleagues wrote in their study on the pathogenic mechanisms underlying IPF. “Normal wound healing involves the recruitment of fibroblasts, deposition of the extracellular matrix (ECM), and differentiation of myofibroblasts, which secrete collagen and generate contractile force for wound closure.”
Moss and colleagues were describing how wound healing in the lungs takes place under normal circumstances. In IPF, we know for certain that this does not take place, even if we still do not have a firm grip on why.
The Role of the Immune System
Smigiel and Parks authored a study on the mechanisms of wound healing and fibrosis. “The immune system is a critical component of the varied processes involved in tissue injury and repair,” they wrote. The regenerative power of the immune system should not be underestimated; it is what keeps us alive whenever a foreign pathogen attacks, which is more often than we realize.
The immune response that drives wound healing is a feature that is shared among many organs, including the lungs, the gastrointestinal tract, and the heart. The processes that dictate tissue remodeling are likewise similar across a number of diseases, including IPF, scleroderma, liver cirrhosis, and myocardial infarction.
Upon damage, the immune system sends signals for the inflammatory cells to be sent to the site of injury. “These signals stimulate the ability of innate immune leukocytes, predominantly macrophages and neutrophils, to migrate across the endothelium, through the vascular wall and interstitium, and for many tissues, across the mucosal/epithelial barrier and into lumenal spaces,” Smigiel and Parks wrote.
Aberrant Wound Repair
So an immunological army is mobilized by the immune system to neutralize an attack or an injury. What comes next is straightforward: the inflammatory response to tissue damage is carried out, and in a relatively short period of time, homeostasis is achieved.
“However, in cases of aberrant repair without proper regulation, chronic wounds and fibrosis ensue,” Smigiel and Parks wrote. This is where the problem begins. Profibrotic cytokines are released, causing the activation of resident fibroblasts and pericytes into ECM-producing myofibroblasts. This results in ECM deposition and fibrosis.
“Fibrotic diseases are typically characterized by upregulation of TGF-β signaling, which promotes recruitment of fibrotic mesenchymal cells and inflammatory mediators, stimulating ECM deposition,” Moss et al wrote.
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Let’s take a closer look at the transition of fibroblasts into myofibroblasts. This is a normal event in wound healing as myofibroblasts play a significant role in generating the contractile force needed for wound closure. They are also associated with the deposition of collagen.
In IPF, the myofibroblasts drive fibrosis and disease progression. A number of signaling pathways contribute to the process of myofibroblast differentiation and apoptosis resistance, including TGF-β, epidermal growth factor, and platelet-derived growth factor (PDGF) receptor. Dysregulation of autophagy, metabolism, and cellular senescence then occur in these IPF myofibroblasts.
‘Characteristics of Senescence’
Waters and colleagues described in detail the consequence of fibroblast senescence in IPF pathology. They wrote, “Within the last few years, several publications have characterized IPF-derived fibroblasts and compared them to age-matched controls. All have concluded that IPF-derived fibroblasts exhibit multiple characteristics of senescence.”
Senescent myofibroblasts can accumulate as part of the normal wound healing process. A study on animal models demonstrated that senescent myofibroblasts proliferated in response to an injuring stimulus. The senescent myofibroblasts limited the accumulation of fibrotic tissue and aided in the resolution of fibrosis, which is to be expected in normal wound healing. However, in IPF, the presence of senescent fibroblasts results in the excessive deposition of the ECM.
The pathological role of senescent fibroblasts in IPF is the reason why Waters et al label IPF as an “age-associated disease.” Why is it that senescent fibroblasts support tissue homeostasis in some cases but drive pathology in others? The reasons are unclear, but “it may be that immune clearance of senescent fibroblasts is compromised as a result of a preexisting pathology or because of a late-onset genetic manifestation in a similar fashion to Huntington’s disease,” Waters and colleagues wrote.
In this article, we have detailed what we know about how aberrant wound healing results in the characteristic fibrosis seen in IPF. What is less clear is what drives this aberrant wound healing process in the first place, a subject that will no doubt continue to be a topic of research.
Moss BJ, Ryter SW, Rosas IO. Pathogenic mechanisms underlying idiopathic pulmonary fibrosis. Annu Rev Pathol. Published online November 23, 2021. doi:10.1146/annurev-pathol-042320-030240
Smigiel KS, Parks WC. Macrophages, wound healing, and fibrosis: recent insights. Curr Rheumatol Rep. 2018;20(4):17. doi:10.1007/s11926-018-0725-5
Waters DW, Blokland KEC, Pathinayake PS, et al. Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2018;315(2):L162-L172. doi:10.1152/ajplung.00037.2018