Injury-specific inflammation leads to organ-specific fibrosis

Tissue fibrosis is the excessive accumulation of extracellular matrix (ECM) that can lead to changes in tissue structure and loss of organ function. Usually, fibrosis ensues from a wound-healing response to acute or chronic injury, independently of the underlying etiology, and can affect every organ system. While fibrosis shares histomorphological parallels across organs, such as excessive deposition of collagen, it also displays tissue-specific characteristics. Numerous reports confirm the presence of common fibrosis pathways across organs, namely, transforming growth factor-β (TGBβ), platelet-derived growth factor (PDGF), Wnt, and hedgehog signaling (3). Nonetheless, each organ also has unique features of fibrosis (6, 9). Several factors may contribute for these differences. For example, fibroblasts, which are the cells responsible for the homeostasis of the ECM, become activated during disease/injury and are the principal source of ECM in fibrosis (1); however, fibroblasts differ among organs and display heterogenous phenotypes within single organs (2). Thus, it is plausible that fibroblasts from distinct organs may secrete ECM that leads to fibrosis via different pathways. Moreover, not all injuries are made equal; tissue damage results from different types of stimuli, and how it develops and heals is dependent on the local (and systemic) microenvironment. As tissue fibrosis is a significant global health problem that both associates with nearly all forms of organ disease and often leads to organ malfunction, there is a high medical need for effective antifibrotic therapeutics. Current strategies focus on targeting the common mechanisms and core pathways that are activated across different fibroproliferative diseases. Yet, the complexity and tissue specificity of fibrosis has made drug development very challenging and, so far, the quest for the “one fits all” antifibrotic drug has been slow. The field is still plagued with unanswered questions, and comprehensive knowledge is needed on how disease/injury and organ specificity affects development of fibrosis.

A large body of evidence shows a dynamic interplay between inflammation and fibrosis. While timely inflammation is essential to initiate the wound-healing process, resolution of inflammation is also essential since failure to resolve leads to chronic inflammation, extended tissue destruction, and progressive fibrosis. In a recent issue of the American Journal of Physiology-Heart and Circulatory Physiology, O’Brien and colleagues (7) used a murine model to demonstrate that myocardial fibrosis is preceded by an inflammatory profile distinct from what occurs during development of pulmonary fibrosis (PF). Their goal was twofold: first, to investigate which factors drive inflammatory cell recruitment in a pressure overload (PO) model of cardiac fibrosis, and second, to determine whether those inflammatory factors are injury specific. To that fact, the authors used two well-established models of organ fibrosis: left ventricular PO-induced hypertrophy to cause cardiac fibrosis and silica-instilled PF. Quantification of protein levels of a panel of cytokines and chemokines revealed that while some cytokines were elevated in both models (CXCL-9, CXCL-10, LIF, MCP-1, and TIMP-1), 8 factors were exclusively elevated in cardiac fibrosis (e.g., CCL11, CCL12, and IL16) and 13 factors were uniquely increased in PF (e.g., CCL-3, CXCL-2, and TNFα). Noteworthy, the cardiac fibrosis cytokine signature identified by O’Brien et al. was consistent with established profiles associated with recruitment of M₂ macrophages and Th1 T cells to nonischemic myocardium in heart failure (1). This study further supports the notion that both the type of injury and the type of organ dictate the progression of tissue healing, including the inflammatory and fibrotic responses. Targeting the proinflammatory response has been shown to mitigate hypertrophy-induced cardiac dysfunction and remodeling. In view of the novel inflammatory profiles described by O’Brien and colleagues, the targeting of inflammatory signaling pathways that associate with tissue-specific fibrosis may be necessary to effectively decrease and/or reverse tissue fibrosis.

Disease-specific triggers initiate tissue damage that is sensed by resident cells, including fibroblasts, endothelial cells, and resident inflammatory cells. These cells release soluble factors, such as cytokines and chemokines, which recruit circulating inflammatory cells that, in turn, release more soluble factors. The inflammatory response is very complex and comprises a vascular phase (extravasation), a cellular phase, and a resolution phase. Since each organ comprises several cell types, including specialized tissue cells, it is not surprising that after extravasation, the interaction between inflammatory cells and resident cells will activate distinct signaling pathways and lead to secretion of unique inflammatory profiles (Fig. 1). These inflammatory factors and cells are essential mediators of the reparative response and will drive fibrosis. With that in mind, CCL11 and CCL12 may be of specific interest as potential targets for the treatment of nonischemic cardiac fibrosis. CCL11 has also been reported to directly associate with myocardial fibrosis during heart transplant rejection (10), and CCL12 is overexpressed during cardiac hypertrophy (5). It would be interesting to see whether the use of monoclonal antibodies against these cytokines would have beneficial effects in different models of cardiac fibrosis. Because of the strong relationship between inflammation and fibrosis, efforts on drug development targeting fibrosis have included anti-inflammatory drugs. Unfortunately, several clinical trials testing anti-inflammatory drugs in fibroproliferative disease patients did not show beneficial effects. Carlumab, a monoclonal antibody against CCL2, was used to treat idiopathic pulmonary fibrosis (IPF) patients (Phase 2 Clinical Trial NCT00786201) without any significant effect (8); similarly, IFN-γ 1b (NCT00047658, NCT00043303, and NCT00043316) was delivered to IPF, cystic fibrosis, and liver fibrosis patients without benefit. On the other hand, nintedanib (a tyrosine kinase inhibitor) and pirfenidone (TGFβ pro-protein convertase furin inhibitor) have shown promising results by slowing the decline in lung function and reducing the risk of acute respiratory deteriorations in IPF patients (4).

Fig. 1.

Diagram showing different types of fibroproliferative diseases across organs. For each organ, example of resident cell types is depicted that during tissue healing would directly interact with inflammatory cells. Image created with BioRender.com.

In the last decade, knowledge regarding the physiology of tissue fibrosis has advanced considerably. The discovery that, in some tissues, fibrosis can be reversible has fueled research in the field. Major areas of focus include fibroblast differentiation and regulation of myofibroblasts, deposition and turnover of ECM, the role of inflammation in fibrosis, and the roles of pro- and antifibrotic factors. Despite significant advancements, there are still major challenges in the quest to develop antifibrotic therapeutics. Namely, to better understand the mechanisms promoting fibrosis, it is necessary to thoroughly define common mechanisms among organs and mechanisms that are either tissue specific or disease specific. Additionally, as demonstrated by O’Brien and colleagues, the transition from inflammation to fibrosis differs in different diseases and/or organs. A deeper understanding of the mechanisms driving both processes and of the sequence of events could help us identify possible therapeutic targets and increase treatment possibilities. The complexity of development and progression of fibrosis make the design of a successful “one fits all” drug type unlikely. Combination therapy and multifactorial drugs that target more than one pathway, for instance, the simultaneous targeting of one common fibrotic pathway and one organ/injury-specific mechanism, will conceivably provide the highest patient benefit.