3.29 ). It may be responsible for substantial organ dysfunction and even organ failure.
As discussed earlier, the major cytokine involved in fibrosis is TGF-β. The mechanisms that lead to increased TGF-β activity in fibrosis are not precisely known, but cell death by necrosis or apoptosis and the production of ROS seem to be important triggers, regardless of the tissue. The cells that produce collagen in response to TGF-β stimulation may vary depending on the tissue. In most organs, such as in the lung and kidney, myofibroblasts are the main source of collagen, but stellate cells are the major collagen producers in liver cirrhosis.
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Fig. 3.28 Clinical examples of excessive scarring and collagen deposition.
(A) Hypertrophic scar. (B) Keloid. (C) Microscopic appearance of a keloid. Note the thick connective tissue deposition in the dermis. (A–B from Eming SA, Margin P, Tomic-Canic M: Wound repair and regeneration: mechanisms,  signaling, and translation, Sci Transl Med 6:265, 2014, p. 2.)
Fibrotic disorders include diverse chronic and debilitating diseases such as liver cirrhosis, systemic sclerosis (scleroderma), fibrosing diseases of the lung (idiopathic pulmonary fibrosis, pneumoconioses, and drug-or  radiation-induced pulmonary fibrosis), end-stage kidney disease, and constrictive pericarditis. These conditions are discussed in the relevant chapters later in the book. Because fibrosis is the major cause of morbidity and death in these conditions, there is great interest in the development of anti-fibrotic drugs.
The main phases of cutaneous wound healing are inflammation, formation of granulation tissue, and ECM remodeling.
Cutaneous wounds can heal by primary union (first intention) or secondary union (secondary intention); secondary healing involves more extensive scarring and wound contraction.
Tissue injury, loss of epithelial integrity
Fig. 3.29 Mechanisms of fibrosis. Persistent tissue injury leads to chronic inflammation and loss of tissue architecture. Cytokines produced by macrophages and other leukocytes stimulate the migration and proliferation of fibroblasts and myofibroblasts and the deposition of collagen and other extracellular matrix proteins. The net result is replacement of normal tissue by fibrosis.
Wound healing can be altered by many conditions, particularly infection and diabetes; the type, volume, and location of the injury are important factors that influence the healing process.
Excessive production of ECM can cause keloids in the skin.
Persistent stimulation of collagen synthesis in chronic inflammatory diseases leads to tissue fibrosis, often with extensive loss of the tissue and functional impairment.
Alitalo K: The lymphatic vasculature in disease, Nat Med 17:1371– 1380, 2011. [An excellent review of the cell biology of lymphatic vessels, their functions in immune and inflammatory reactions, and their roles in inflammatory, neoplastic, and other diseases.]
Dennis EA, Norris PC: Eicosanoid storm in infection and inflammation, Nat Rev Immunol 15:511, 2015. [A review of the proand antiinflammatory activities of eicosanoids.]
Duffield JS, Lupher M, Thannickal VJ, et al: Host responses in tissue repair and fibrosis, Ann Rev Pathol Mech Dis 8:241, 2013. [An overview of the cellular mechanisms of fibrosis, with an emphasis on the role of the immune system in fibrotic reactions to chronic infections.]