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Dual inhibition of the MEK/ERK and PI3K/AKT pathways prevents pulmonary GVHD suppressing perivenulitis and bronchiolitis.

ABSTRACT: Patients with pulmonary graft-versus-host disease (pGVHD) have a poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, pGVHD pathogenesis is not fully elucidated in humans, and currently available immunosuppressants are inadequately effective. We performed pathologic evaluation of lung specimens from 45 allo-HSCT recipients with pGVHD who underwent lung transplantation. Patient pathology was characterized by bronchiolitis and subpleural perivascular inflammation, with B-cell, monocyte, and T-cell accumulation around bronchioles. Bronchiolitis, perivascular inflammation, and peribronchial macrophage aggregation were also identified in a murine pGVHD model after transplant of bone marrow cells and splenocytes from C57BL/6 to B10.BR mice. Among mitogen-activated protein kinase kinase (MEK) inhibitors, cobimetinib, but not trametinib, improved survival rates. Cobimetinib attenuated bronchiolitis, improved airway resistance and lung compliance in the mice, and suppressed activation of B cells and tumor necrosis factor α production by monocytes in vitro; these features were not suppressed by trametinib or tacrolimus. Furthermore, cobimetinib suppressed activation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling, resulting in B-cell and monocyte suppression. Dual inhibition of the MEK/extracellular signal-regulated kinase (ERK) and PI3K/AKT pathways using a combination of trametinib and the PI3K inhibitor taselisib strongly suppressed B-cell activation in vitro and improved mouse survival rates compared with vehicle or monotherapy with trametinib or taselisib. Imaging mass cytometry of human pGVHD revealed that T cells around bronchioles were positive for phosphorylated ERK, whereas B cells were positive for phosphorylated AKT. Thus, perivascular inflammation and bronchiolitis mediated by activation of the MEK/ERK and PI3K/AKT pathways are essential for pGVHD and represent a potential novel therapeutic target in humans.

SUBMITTER: Muranushi H

PROVIDER: S-EPMC9830178 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Dual inhibition of the MEK/ERK and PI3K/AKT pathways prevents pulmonary GVHD suppressing perivenulitis and bronchiolitis.

Muranushi Hiroyuki H Shindo Takero T Chen-Yoshikawa Toyofumi F TF Yoshizawa Akihiko A Thi Ngo Huong H Gochi Fumiaki F Date Hiroshi H Takaori-Kondo Akifumi A

Blood advances 20230101 1

Patients with pulmonary graft-versus-host disease (pGVHD) have a poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, pGVHD pathogenesis is not fully elucidated in humans, and currently available immunosuppressants are inadequately effective. We performed pathologic evaluation of lung specimens from 45 allo-HSCT recipients with pGVHD who underwent lung transplantation. Patient pathology was characterized by bronchiolitis and subpleural perivascular in ...[more]

PMID: 35468620

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Dual inhibition of the MEK/ERK and PI3K/AKT pathways prevents pulmonary GVHD suppressing perivenulitis and bronchiolitis.

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Dual inhibition of the MEK/ERK and PI3K/AKT pathways prevents pulmonary GVHD suppressing perivenulitis and bronchiolitis.

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