RationaleIdiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in IPF pathogenesis. We have reported anti-col(V) immunity in IPF patients. The objective of our study was to determine the specificity of col(V) expression profile and anti-col(V) immunity relative to col(I) in clinical IPF and the efficacy of nebulized col(V) in pre-clinical IPF models.MethodsCol(V) and col(I) expression profile was analyzed in normal human and IPF tissues. C57-BL6 mice were intratracheally instilled with bleomycin (0.025 U) followed by col(V) nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses.ResultsCompared to normal lungs, IPF lungs had higher protein and transcript expression of the alpha 1 chain of col(V) and col(I). Systemic anti-col(V) antibody concentrations, but not of anti-col(I), were higher in IPF patients. Nebulized col(V), but not col(I), prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. Col(V) treatment suppressed systemic levels of anti-col(V) antibodies, IL-6 and TNF-α; and local Il-17a transcripts. Compared to controls, nebulized col(V)-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-α and IFN-γ. In a clinically relevant established fibrosis model, nebulized col(V) decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis (Tgf-β, Il-1β, Pdgfb), matrix (Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3) and members of the TGF-β superfamily (Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb).ConclusionsAnti-col(V) immunity is pathogenic in IPF, and col(V)-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- β-related signaling pathways.

Obliterative bronchiolitis (OB) post lung transplantation involves IL-17 regulated autoimmunity to type V collagen and alloimmunity, which could be enhanced by complement activation. However, the specific role of complement activation in lung allograft pathology, IL-17 production, and OB are unknown. The current study examines the role of complement activation in OB. Complement regulatory protein (CRP) (CD55, CD46, Crry/CD46) expression was down regulated in human and murine OB; and C3a, a marker of complement activation, was up regulated locally. IL-17 differentially suppressed Crry expression in airway epithelial cells in vitro. Neutralizing IL-17 recovered CRP expression in murine lung allografts and decreased local C3a production. Exogenous C3a enhanced IL-17 production from alloantigen or autoantigen (type V collagen) reactive lymphocytes. Systemically neutralizing C5 abrogated the development of OB, reduced acute rejection severity, lowered systemic and local levels of C3a and C5a, recovered CRP expression, and diminished systemic IL-17 and IL-6 levels. These data indicated that OB induction is in part complement dependent due to IL-17 mediated down regulation of CRPs on airway epithelium. C3a and IL-17 are part of a feed forward loop that may enhance CRP down regulation, suggesting that complement blockade could be a therapeutic strategy for OB.

Objectives: To compare pain after operative versus nonoperative pelvic ring injuries with unilateral sacral fractures. Design: Prospective, multicenter, observational. Setting: Sixteen trauma centers. Patients/Participants: Skeletally mature patients with pelvic ring injury and minimally displaced unilateral zone 1 or 2 sacral fractures and without anteroposterior compression injuries. Main Outcome Measurements: Pelvic displacement was documented on injury plain radiographs and computed tomography scans; a 10 point Visual Analog Scale (VAS) was used to evaluate pain was obtained in the anterior and posterior pelvic ring during the time of union (12 weeks). Results: One hundred ninety-four patients with unilateral sacral fractures displaced less than 5 mm, mean age of 38.7, and mean Injury Severity Score of 14.5 were included. Ninety-nine percent had lateral compression injuries, and 62% were in zone 1. Seventy-four percent were treated nonoperatively. Nonoperative patients had more zone 1 fractures (71%, P = 0.004). Nonoperative patients reported mean VAS 2.7 points higher in the posterior pelvis (P = 0.01) and 1.9 points higher anteriorly (P = 0.11) 24 hours after injury compared with patients treated operatively. After 3 months, nonoperative patients reported higher VAS scores than operative patients: 4.0 versus 2.9 posteriorly (P = 0.019) and 3.2 versus 2.3 anteriorly (P = 0.035). Conclusions: For sacrum fractures with minimal or no displacement, slight differences in the VAS were noted within 24 hours after injury or surgery, but limited differences were seen at 3 months for either operatively treated minimally or undisplaced sacrum fractures. It is unknown whether this represents clinical relevance. These differences were below the minimally important clinical difference for VAS scores for other orthopaedic conditions. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Objectives: To quantify the acute immunologic biomarker response in multiply injured patients with axial and lower extremity fractures and to explore associations with adverse short-term outcomes including organ dysfunction and nosocomial infection (NI). Design: Prospective cohort study. Setting: Level 1 academic trauma center. Patients: Consecutive multiply injured patients, 18–55 years of age, with major pelvic and lower extremity orthopaedic injuries (all pelvic/acetabular fractures, operative femur and tibia fractures) that presented as a trauma activation and admitted to the intensive care unit from April 2015 through October 2016. Sixty-one patients met inclusion criteria. Intervention: Blood was collected upon presentation to the hospital and at the following time points: 8, 24, 48 hours, and daily during intensive care unit admission. Blood was processed by centrifugation, separation into 1.0-mL plasma aliquots, and cryopreserved within 2 hours of collection. Main Outcome Measurements: Plasma analyses of protein levels of cytokines/chemokines were performed using a Luminex panel Bioassay of 20 immunologic mediators. Organ dysfunction was measured by the Marshall Multiple Organ Dysfunction score (MODScore) and nosocomial infection (NI) was recorded. Patients were stratified into low (MODS ≤ 4; n = 34) and high (MODS > 4; n = 27) organ dysfunction groups. Results: The MODS >4 group had higher circulating levels of interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), IL-1 receptor antagonist (IL-1RA), and monokine induced by interferon gamma (MIG) compared with the MODS ≤4 group at nearly all time points. MODS >4 exhibited lower levels of IL-21 and IL-22 compared with MODS ≤4. Patients who developed NI (n = 24) had higher circulating concentrations of IL-10, MIG, and high mobility group box 1 (HMGB1) compared with patients who did not develop NI (n = 37). Conclusions: Temporal quantification of immune mediators identified 8 biomarkers associated with greater levels of organ dysfunction in polytrauma patients with major orthopaedic injuries. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.