Targeting the Canonical Nuclear Factor-κB Pathway with a High-Potency IKK2 Inhibitor Improves Outcomes in a Mouse Model of Idiopathic Pneumonia Syndrome

Kenneth A. Fowler, Corey M. Jania, Stephen L. Tilley, Angela Panoskaltsis-Mortari, Albert S. Baldwin, Jonathan S. Serody, James M. Coghill

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Idiopathic pneumonia syndrome (IPS) is a noninfectious inflammatory disorder of the lungs that occurs most often after fully myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). IPS can be severe and is associated with high 1-year mortality rates despite existing therapies. The canonical nuclear factor-(NF) κB signaling pathway has previously been linked to several inflammatory disorders of the lung, including asthma and lung allograft rejection. It has never been specifically targeted as a novel IPS treatment approach, however. Here, we report that the IκB kinase 2 (IKK2) antagonist BAY 65-5811 or “compound A,” a highly potent and specific inhibitor of the NF-κB pathway, was able to improve median survival times and recipient oxygenation in a well-described mouse model of IPS. Compound A impaired the production of the proinflammatory chemokines CCL2 and CCL5 within the host lung after transplantation. This resulted in significantly lower numbers of donor lung infiltrating CD4+ and CD8+ T cells and reduced pulmonary inflammatory cytokine production after allograft. Compound A's beneficial effects appeared to be specific for limiting pulmonary injury, as the drug was unable to improve outcomes in a B6 into B6D2 haplotype-matched murine HSCT model in which recipient mice succumb to lethal acute graft-versus-host disease of the gastrointestinal tract. Collectively, our data suggest that the targeting of the canonical NF-κB pathway with a small molecule IKK2 antagonist may represent an effective and novel therapy for the specific management of acute lung injury that can occur after allogeneic HSCT.

Original languageEnglish (US)
Pages (from-to)569-580
Number of pages12
JournalBiology of Blood and Marrow Transplantation
Volume23
Issue number4
DOIs
StatePublished - Apr 1 2017

Bibliographical note

Funding Information:
This work was supported by the following NIH grants: 5K12CA120780-05 and 5K08HL111205-04 to JMC; R01CA166794 and R01HL115761 to JSS

Keywords

  • Chemokines
  • Graft-versus-host disease
  • Idiopathic pneumonia syndrome
  • Lymphocyte trafficking
  • Nuclear factor-kB pathway

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