The Processes and Mechanisms of Cardiac and Pulmonary Fibrosis

Abstract

Fibrosis is the formation of fibrous connective tissue in response to injury. It is characterized by the accumulation of extracellular matrix components, particularly collagen, at the site of injury. Fibrosis is an adaptive response that is a vital component of wound healing and tissue repair. However, its continued activation is highly detrimental and a common final pathway of numerous disease states including cardiovascular and respiratory disease. Worldwide, fibrotic diseases cause over 800,000 deaths per year, accounting for ~45% of total deaths. With an aging population, the incidence of fibrotic disease and subsequently the number of fibrosis-related deaths will rise further. Although, fibrosis is a well-recognized cause of morbidity and mortality in a range of disease states, there are currently no viable therapies to reverse the effects of chronic fibrosis. Numerous predisposing factors contribute to the development of fibrosis. Biological aging in particular, interferes with repair of damaged tissue, accelerating the transition to pathological remodeling, rather than a process of resolution and regeneration. When fibrosis progresses in an uncontrolled manner, it results in the irreversible stiffening of the affected tissue, which can lead to organ malfunction and death. Further investigation into the mechanisms of fibrosis is necessary to elucidate novel, much needed, therapeutic targets. Fibrosis of the heart and lung make up a significant proportion of fibrosis-related deaths. It has long been established that the heart and lung are functionally and geographically linked when it comes to health and disease, and thus exploring the processes and mechanisms that contribute to fibrosis of each organ, the focus of this review, may help to highlight potential avenues of therapeutic investigation.

Keywords: acute respiratory distress syndrome; cardiac fibrosis; heart; heart failure; idiopathic pulmonary hypertension; lung; myocardial infarction; pulmonary fibrosis.

Figure 1

Commonly secreted pro-fibrogenic growth factors, inflammatory proteins, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) during the fibrotic processes of myocardial infarction and idiopathic pulmonary fibrosis. Fibrotic disease of the heart and lung is the result of a range of cellular and molecular responses activated by tissue injury. The fibrotic process is tightly regulated and involves three distinct phases: the inflammatory, proliferative, and maturation phase. During the inflammatory and proliferative phases, a number of pro-fibrogenic, and inflammatory mediators are released to recruit and activate reparative mesenchymal cells such as fibroblasts and myofibroblasts. These cells aid scar formation and maintains the structural integrity of the tissue. MMPs and TIMPs are released by fibroblasts. Their release can be further mediated by various chemokines, cytokines, and growth factors released during the remodeling process. MMPs and TIMPs work in concert to control the remodeling and degradation of extracellular matrix proteins at the site of injury. ANGII, Angiotensin II; CTGF, Connective Tissue Growth Factor; FGFs, Fibroblast Growth Factors; PDGF, Platelet-Derived Growth Factor; TGF, Transforming Growth Factor; VEGF, Vascular Endothelial Growth Factor; IFN-γ, Interferon-γ; IL, Interleukin; TNF, Tumor Necrosis Factor.