Abstract
Fibrosing diseases, such as pulmonary fibrosis, cardiac fibrosis, myelofibrosis, liver fibrosis, and renal fibrosis are chronic and debilitating conditions and are an increasing burden for the healthcare system. Fibrosis involves the accumulation and differentiation of many immune cells, including macrophages and fibroblast-like cells called fibrocytes. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP also promotes the formation of immuno-regulatory Mreg macrophages. To elucidate the endogenous function of SAP, we used bleomycin aspiration to induce pulmonary inflammation and fibrosis in mice lacking SAP. Compared to wildtype C57BL/6 mice, we find that in Apcs-/- “SAP knock-out” mice, bleomycin induces a more persistent inflammatory response and increased fibrosis. In both C57BL/6 and Apcs-/- mice, injections of exogenous SAP reduce the accumulation of inflammatory macrophages and prevent fibrosis. The types of inflammatory cells present in the lungs following bleomycin-aspiration appear similar between C57BL/6 and Apcs -/- mice, suggesting that the initial immune response is normal in the Apcs-/- mice, and that a key endogenous function of SAP is to promote the resolution of inflammation and fibrosis.
Highlights
Fibrosing diseases, such as pulmonary fibrosis, cardiac fibrosis associated with hypertensive heart disease, primary myelofibrosis of the bone marrow, liver fibrosis, and renal fibrosis are chronic and debilitating conditions and are an increasing burden for the healthcare system [1]
The inflammatory cells present in the lungs after bleomycin aspiration appear similar between C57BL/6 and Apcs-/- mice, suggesting that the initial response to the insult is independent of serum amyloid P component (SAP), and that a key function of SAP is to promote the resolution of inflammation and fibrosis
We found that compared to C57BL/6 mice, Apcs-/- mice had a persistent inflammatory response and increased fibrosis in the lungs after bleomycin aspiration
Summary
Fibrosing diseases, such as pulmonary fibrosis, cardiac fibrosis associated with hypertensive heart disease, primary myelofibrosis of the bone marrow, liver fibrosis, and renal fibrosis are chronic and debilitating conditions and are an increasing burden for the healthcare system [1]. Fibrosis is mediated by infiltration of blood leukocytes into a tissue, activation and/or appearance of fibroblast-like cells, tissue remodeling, and deposition of extracellular matrix proteins such as collagen [1,4]. Following their recruitment from the blood into a tissue, monocytes can differentiate into macrophages, dendritic cells, or fibrocytes [4,5]. Regulatory M2reg macrophages are generally anti-inflammatory, secrete IL-10, and are important during the resolution phase of inflammation [1,9] These subsets can be viewed as separate, they may be more accurately thought of as a continuum, and may convert from one subset to another depending on the stimuli in an environment [7,9]
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