American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Sep 2022
Tacrolimus Prevents Mechanical and Humoral Alterations in Brain Death-Induced Lung Injury in Pigs.
Rationale: Donor brain death-induced lung injury may compromise graft function after transplantation. Establishing strategies to attenuate lung damage remains a challenge because the underlying mechanisms remain uncertain. Objectives: The effects of tacrolimus pretreatment were evaluated in an experimental model of brain death-induced lung injury. ⋯ Tacrolimus pretreatment prevented increases in the ratio of IL-6 to IL-10, VCAM1 (vascular cell adhesion molecule 1), circulating concentrations of IL-1β, and glycocalyx-derived molecules. Tacrolimus partially decreased apoptosis (Bax [Bcl2-associated X apoptosis regulator]-to-Bcl2 [B-cell lymphoma-2] ratio [P = 0.07] and number of apoptotic cells in the lungs [P < 0.05]) but failed to improve LIS. Conclusions: Immunomodulation through tacrolimus pretreatment prevented pulmonary capillary hypertension as well as the activation of inflammatory and apoptotic processes in the lungs after brain death; however, LIS did not improve.
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Am. J. Respir. Crit. Care Med. · Sep 2022
Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis.
Rationale: Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated. Objectives: On the basis of our observation that lung fibroblasts express TBXA2R (thromboxane-prostanoid receptor) during fibrosis, we investigated the role of TBXA2R signaling in fibrotic remodeling. Methods: We identified TBXA2R expression in lungs of patients with IPF and mice and studied primary mouse and human lung fibroblasts to determine the impact of TBXA2R signaling on fibroblast activation. ⋯ In vivo treatment with the TBXA2R antagonist ifetroban reduced profibrotic signaling in the lungs, protected mice from lung fibrosis in three preclinical models (bleomycin, Hermansky-Pudlak mice, and radiation-induced fibrosis), and markedly enhanced fibrotic resolution after bleomycin treatment. Conclusions: TBXA2R links oxidative stress to fibroblast activation during lung fibrosis. TBXA2R antagonists could have utility in treating pulmonary fibrosis.