title: Extracellular matrix alterations and acute inflammation; developing in parallel during early induction of pulmonary fibrosis.
abstract: Pulmonary fibrosis is a hallmark of several systemic diseases such as systemic sclerosis. Initiation and early development is not well characterized, as initiation usually is unnoticed in patients, yet fibrosis has been considered a late event, occurring after an inflammatory phase. By utilizing an animal model, the starting point can be defined and the initiation process and early development thoroughly investigated. To investigate these processes from a systemic perspective, we choose a systemic administration route, instead of the more commonly used local administration. The aim of this work was to study the initiation of pulmonary fibrosis in an animal model and to investigate early alterations in connective tissue, cell turnover and acute immune response in lung parenchyma. Animals were injected subcutaneously with bleomycin, three times a week (w) for 1-4w (controls received saline). Total collagen was histologically assessed by Picro Sirius Red and Masson's Trichrome, collagen production by antibodies directed against N-terminal of procollagens I and III, proliferation by labeling with proliferating cell nuclear antigen, apoptosis by TUNEL and innate immunity by detecting neutrophils and macrophages. Total collagen was significantly increased at 1, 2 and 4w compared with controls. Procollagen I, was increased at 1w and remained increased, whereas procollagen III-staining was increased at 2w, compared with controls. Myofibroblasts were increased at all times as were proliferation, whereas apoptosis was increased from 2w. Neutrophils peaked at 1w (2779±820 cells/mm²) and gradually decreased, whereas macrophages peaked at 2w (135±29 cells/mm²). Subcutaneously administered bleomycin induces rapid alterations in connective tissue and cell turnover, suggesting a plasticity of the connective tissue. A transient neutrophilia is detected and increased number of macrophages likely represents a clearance process of said neutrophils. The study suggests fibrosis initiation and acute inflammation to occur in parallel in this model.
authors.affiliation: Section of Rheumatology, Department of Clinical Science, Lund University, Lund, Sweden. Kristina.Rydell-Tormanen@med.lu.se
authors.forename: Kristina
authors.initials: K
authors.lastname: Rydell-Törmänen
authors.forename: Kristofer
authors.initials: K
authors.lastname: Andréasson
authors.forename: Roger
authors.initials: R
authors.lastname: Hesselstrand
authors.forename: Juha
authors.initials: J
authors.lastname: Risteli
authors.forename: Dick
authors.initials: D
authors.lastname: Heinegård
authors.forename: Tore
authors.initials: T
authors.lastname: Saxne
authors.forename: Gunilla
authors.initials: G
authors.lastname: Westergren-Thorsson
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000008:administration & dosage / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D007279:Injections, Subcutaneous; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D001761:Bleomycin; D003094:Collagen