Choi, Kukbin

Abstract Rationale Extracellular matrix (ECM) accumulation results from an imbalance between ECM deposition and degradation, due to persistently increased ECM synthesis or reduced resorption. Fibroblasts, as key regulators of ECM homeostasis in both health and disease, are essential targets to rebalance ECM turnover. Recent findings indicate that fibroblasts are regulated by immune cells, which can influence ECM deposition. Specifically, myeloperoxidase (MPO), an enzyme produced by neutrophils, has been shown to enhance fibroblast-driven ECM accumulation in various diseases. In patients with radiographic Interstitial Lung Disease (ILD), elevated MPO levels have been correlated with reduced lung capacity (Cantin et al., 1987), while recent studies report increased MPO levels in the bronchoalveolar lavage fluid of ILD patients (Ngo et al., EJROR 2024). Additionally, MPO and related immune dysregulation proteins are found in fibrotic alveoli in Idiopathic Pulmonary Fibrosis (IPF) (Herrera et al., JCI Insight 2022). These findings suggest an association between MPO and lung fibrosis, yet it remains uncertain whether MPO directly influences ECM accumulation in fibrotic progression. Methods Patient tissue and serum samples were collected with consent, and MPO levels were quantified using ELISA and immunofluorescence techniques. Biochemical assays were performed using MPO isolated from human leukocytes, recombinant cathepsin K, and hydrogen peroxide to investigate whether MPO influences cathepsin K activity. Precision cut lung slices (PCLS) were prepared from untreated C57BL/6 mice and treated with transforming growth factor-beta (TGFβ) and/or MPO for four days, with cathepsin K activity assessed using fluorescence assays. Additionally, MPO-knockout and wild-type mice received intratracheal bleomycin, and after 14 days, cathepsin K activity was quantified via in vivo imaging. Collagen content, as an indicator of fibrosis, was measured by quantifying hydroxyproline in harvested lung tissue. Results/Discussion/Conclusion Increased MPO levels were observed in immunofluorescent-stained samples (57%; 4/7) and serum samples (30%; 3/10) from IPF patients. Biochemical assays demonstrated that physiological levels of MPO (0.2 µg/ml) combined with H2O2 reduced recombinant cathepsin K activity by 85%. In PCLS treated with MPO, cathepsin K activity decreased by 50% with or without TGFβ. After bleomycin treatment, wild-type mice showed reduced cathepsin K activity, while MPO-knockout mice maintained activity levels. Both survival and weight loss were similar between wild-type and MPO-knockout mice; however, collagen content was significantly higher in wild-type mice, whereas MPO-knockout mice were protected from bleomycin-induced collagen accumulation. These findings suggest that MPO contributes to ECM accumulation in lung fibrosis, potentially through inhibition of collagenolytic enzymes such as cathepsin K.

Combined heart-lung transplant (HTLx) is the most durable treatment available for end-stage heart and lung failure. Many patients are unable to receive combined organs due to organ availability and allocation policies prioritizing separate heart or lung transplantation. While an average of 45 HTLxs have been performed per year in the United States half the listed patients do not receive organs. Recently, donation after circulatory death (DCD) utilizing normothermic regional perfusion (NRP) has been utilized for heart allografts with excellent results, and here, we present a case utilizing mobile NRP to procure a heart and lung block from a circulatory death donor and successful implantation for a recipient in a separate center.

Acute post-infarction posterior ventricular septal defect (VSD) is associated with high mortality. Furthermore, patients with cardiogenic shock have been reported to have worse outcomes (1). There are conflicting reports about the optimum timing and method of surgical repair (2). Early surgical intervention has been reported to have high mortality, whereas the risk of dying in the waiting period with the medical management is also exponentially high (1). We present a case of post-infarction posterior VSD complicated by cardiogenic shock. The patient was successfully supported with peripheral veno-arterial extracorporeal membrane oxygenator as a bridge to a trans-right atrial repair.

Abstract Background Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase ( HO 1) leads to loss of interstitial cells of Cajal and delayed gastric emptying ( GE ) in non‐obese diabetic mice. Our hypothesis was that hemin upregulation of HO 1 would restore normal GE in humans with gastroparesis. Aims To compare effects of hemin and placebo infusions on HO 1 activity and protein, GE , autonomic function, and gastrointestinal symptoms in diabetic gastroparesis. Methods In a single‐center, double‐blind, placebo‐controlled, randomized clinical trial, we compared intravenous hemin, prepared in albumin, or albumin alone (placebo) in 20 patients, aged 41 ± 5 ( SEM ) years with diabetic gastroparesis. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 additional weeks. Assessments included blood tests for HO 1 protein and enzyme activity levels, GE with 13 C‐spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks. Key Results Nine of 11 patients randomized to hemin completed all study procedures. Compared to placebo, hemin increased HO 1 protein on days 3 ( p = 0.0002) and 7 ( p = 0.008) and HO 1 activity on day 3 ( p = 0.0003) but not after. Gastric emptying, autonomic functions, and symptoms did not differ significantly in the hemin group relative to placebo. Conclusions & Inferences Hemin failed to sustain increased HO 1 levels beyond a week and did not improve GE or symptoms in diabetic gastroparesis. Further studies are necessary to ascertain whether more frequent hemin infusions or other drugs would have a more sustained effect on HO 1 and improve GE .