Sandra Miklos, Gunnar Mueller, Yayi Chang, Thomas E. O

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Presentation transcript:

Pulmonary Function Changes in Experimental Graft-versus-Host Disease of the Lung Sandra Miklos, Gunnar Mueller, Yayi Chang, Thomas E.O. Schubert, Ernst Holler, Gerhard C. Hildebrandt Biology of Blood and Marrow Transplantation Volume 14, Issue 9, Pages 1004-1016 (September 2008) DOI: 10.1016/j.bbmt.2008.06.015 Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Lung injury, survival, and clinical GVHD. Lethally irradiated B6D2F1 mice received SCT with 5 × 106 bone marrow and 6 × 106 splenocytes from either syngeneic (B6D2F1) or allogeneic (C57Bl/6) donors as described in Materials and Methods. (A-B) Pulmonary injury was determined on days +7 and +42 after SCT by using a well-established scoring system and by histopathology; ∗P < .05 (syngeneic [white bar] versus allogeneic [black bar]). Animals were monitored daily for (C) survival and weekly for (D) GVHD clinical scores and (E) weight. ∗P < .05 (syngeneic [dotted line, open triangles] versus allogeneic [solid black line, filled squares]). Data are presented as mean ± SEM. Survival data are combined from 2 independent and comparable experiments; n (syngeneic) = 8, n (allogeneic) = 17 for survival. Histopatholoy data at week 1 are combined from 2 independent experiments (n [syngeneic] = 7, n [allogeneic] = 8) and at week 6 are combined from 3 independent experiments (n [syngeneic] = 7, n [allogeneic] = 16). ∗P < .05. Biology of Blood and Marrow Transplantation 2008 14, 1004-1016DOI: (10.1016/j.bbmt.2008.06.015) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Changes in breathing patterns. Lethally irradiated B6D2F1 mice received SCT with 5 × 106 bone marrow and 6 × 106 splenocytes from either syngeneic (B6D2F1, dotted line, open triangles) or allogeneic (C57Bl/6, solid black line, filled squares) donors as described in Materials and Methods. Respiratory patterns were measured weekly by whole-body plethysmography in conscious, freely moving animals. To compare changes in breathing patterns of allogeneic recipients with syngeneic controls the following parameters were assessed: (A) minute ventilation (MV), (B) tidal volume (TV), (C) respiratory rate (RR), (D) cumulative incidences of MV ≤50% of pre-SCT, (E) peak inspiratory flow (PIF), (F) peak expiratory flow (PEF), (G) cumulative incidences of PIF ≤70% of pre-SCT, (H) cumulative incidences of PEF ≤50% of pre-SCT. For both syngeneic and allogeneic recipients, data shown are expressed as % of baseline values. In addition, changes in allogeneic recipients are demonstrated as % of syngeneic (A-C, E-F). Data are presented as mean ± SEM and are combined from 3 independent comparable experiments; initial n = 13 to 25 per group, minimal n at each time point ≥5; ∗P < .05; ∗∗P < .001. Biology of Blood and Marrow Transplantation 2008 14, 1004-1016DOI: (10.1016/j.bbmt.2008.06.015) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Changes in minute ventilation (MV) and peak inspiratory flow (PIF), but not peak expiratory flow (PEF), are associated with increased mortality after allogeneic SCT. (A-C) Increased mortality in allogeneic recipients given 5 × 106 bone marrow and 6 × 106 splenocytes was associated (A) with MV ≤50% (black solid line) versus MV >50% (black dotted line), (B) PIF ≤70% (black solid line) versus PIF >70% (black dotted line), but (C) not with reductions in PEF (PEF ≤50% [black solid line] versus PEF >50% [black dotted line]). (D) Overall survival in allogeneic recipients was directly related to clinical GVHD severity (GVHD ≥5: black solid line; GVHD <5: black dotted line). (E-G) Clinical GVHD scores ≥5 were associated with (E) MV ≤50% (black solid line) versus MV >50% (black dotted line), (F) PIF ≤70% (black solid line) versus PIF >70% (black dotted line), but (G) not with reductions in PEF (PEF ≤50% [black solid line] versus PEF >50% [black dotted line]). Data presented are combined from 3 independent comparable experiments; total n = 25; ∗P < .05; ∗∗P < .001. Biology of Blood and Marrow Transplantation 2008 14, 1004-1016DOI: (10.1016/j.bbmt.2008.06.015) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Changes in compliance, lung volumes, and flow rates. (A-F) Lethally irradiated B6D2F1 mice received SCT with 5 × 106 bone marrow and 6 × 106 splenocytes from either syngeneic B6D2F1 or allogeneic C57Bl/6 donors, and on day +7 and day +42 PFT were performed as described in Materials and Methods. Lung injury was assessed by changes in (A) VC, (B) FVC, (C) Cchord, (D) FEV50, (E) FEV50/FVC, (F) FEF25. The lowest, second lowest, middle, second highest, and highest box points represent the 10th percentile, 25th percentile, median, 75th percentile, and 90th percentile, respectively. Means are represented by symbols. Data are presented as mean ± SEM and are combined from 2 independent comparable experiments; week 1: n = 7 to 10 per group, week 6: n = 7 to 9 per group. ∗P < .05, ∗∗P < .01, +P = .05. Biology of Blood and Marrow Transplantation 2008 14, 1004-1016DOI: (10.1016/j.bbmt.2008.06.015) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Reduced SP-A levels at 1 and 6 weeks after allo-SCT. (A-B) SP-A levels in the lungs of syngeneic and allogeneic recipients of 5 × 106 bone marrow and 6 × 106 splenocytes were determined at 1 and 6 weeks after transplantation as described in Materials and Methods. Data are combined from 3 comparable experiments (day 7: n = 11 animals per group; day 42: n = 9 syngeneic and 11 allogeneic recipients) and presented as mean ± SE. ∗P < .05. Biology of Blood and Marrow Transplantation 2008 14, 1004-1016DOI: (10.1016/j.bbmt.2008.06.015) Copyright © 2008 American Society for Blood and Marrow Transplantation Terms and Conditions