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Rationale: Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear., Objectives: To describe the incidence, characteristics, and impact of dnDSA after lung transplantation., Methods: We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis., Measurements and Main Results: The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA., Conclusions: dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

Skeletal muscle atrophy in individuals with advanced chronic obstructive pulmonary disease (COPD) is associated with diminished quality of life, increased health resource use, and worsened survival. Muscle wasting results from an imbalance between protein degradation and synthesis, and is enhanced by decreased regenerative repair. We investigated the activation of cellular signaling networks known to mediate muscle atrophy and regulate muscle regenerative capacity in rodent models, in individuals with COPD (FEV(1) < 50% predicted). Nine patients with COPD and nine control individuals were studied. Quadriceps femoris muscle isometric contractile force and cross-sectional area were confirmed to be significantly smaller in the patients with COPD compared with control subjects. The vastus lateralis muscle was biopsied and muscle transcript and/or protein levels of key components of ubiquitin-mediated proteolytic systems (MuRF1, atrogin-1, Nedd4), inflammatory mediators (IkappaBalpha, NF-kappaBp65/p50), AKT network (AKT, GSK3beta, p70S6 kinase), mediators of autophagy (beclin-1, LC3), and myogenesis (myogenin, MyoD, Myf5, myostatin) were determined. Atrogin-1 and Nedd4, two ligases regulating ubiquitin-mediated protein degradation and myostatin, a negative regulator of muscle growth, were significantly increased in the muscle of patients with COPD. MuRF1, Myf5, myogenin, and MyoD were not differentially expressed. There were no differences in the level of phosphorylation of AKT, GSK3beta, p70S6kinase, or IkappaBalpha, activation of NF-kappaBp65 or NF-kappaBp50, or level of expression of beclin-1 or LC3, suggesting that AKT signaling was not down-regulated and the NF-kappaB inflammatory pathway and autophagy were not activated in the COPD muscle. We conclude that muscle atrophy associated with COPD results from the recruitment of specific regulators of ubiquitin-mediated proteolytic pathways and inhibition of muscle growth.

Lung tissue may be an important source of systemic inflammation associated with sepsis and the acute respiratory distress syndrome (ARDS). An ex vivo model of freshly explanted lung tissue in culture was developed to evaluate the ability of lipopolysaccharide (LPS) to directly stimulate lung tissues under conditions where indirect mechanisms such as recruitment of blood-derived inflammatory cells could not be implicated. Under control conditions, lung explants produced a high level of macrophage inflammatory protein-2 (MIP-2). Eight hours after LPS challenge, there were marked increases in the production of tumor necrosis factor-alpha (TNF-alpha) from 0.18 +/- 0.04 to 4.13 +/- 0.23 ng/ml/g tissue (p < 0.05), MIP-2 from 60.0 +/- 7.4 to 165.6 +/- 10.3 ng/ml/g tissue (p < 0.05), and tissue lipid peroxidation (malonaldehyde from 27.6 +/- 2.5 to 48.4 +/- 17.5 microM/g tissue; and 4-hydroxyalkenal from 34.0 +/- 3.0 to 59.7 +/- 18.8 microM/g tissue, both p < 0.05) from lung explants. Treatment with the beta-adrenoreceptor agonist isoproterenol (1 ng/ml) attenuated LPS-induced release of TNF-alpha and lipid peroxidation in association with an increase in intracellular cAMP levels. The adenylate cyclase activator, forskolin, also inhibited LPS-induced changes in TNF-alpha and lipid peroxidation. In conclusion, increasing intracellular levels of cAMP through beta-adrenoreceptor activation can attenuate the acute inflammatory response induced in the lung by LPS. LPS did not significantly impair the beta-adrenoreceptor reactivity in lung explants. Lung explants allow for the quantitative assessment of pulmonary inflammatory responses independent of influences from the circulation, and thus may be a useful ex vivo model to investigate cellular and molecular mechanisms of lung injury.