Ablation of PDE4B Protects from Lung Injury in a Mouse Model of Acute P. aeruginosa Infection

Rationale Non‐selective inhibitors of Type 4 cAMP‐phosphodiesterases (PDE4s) exert well established anti‐inflammatory effects in non‐infectious models of lung inflammation, such as upon exposure to lipopolysaccharide or ovalbumin, and have demonstrated clinical efficacy in the treatment of COPD. However, they also produce side effects, including emesis, nausea, diarrhea, and weight loss, that limit their clinical utility. The PDE4 family comprises 4 subtypes (PDE4A‐D). As each plays unique and non‐overlapping physiological roles, targeting individual subtypes may serve to separate the therapeutically beneficial from side effects resulting from non‐selective PDE4 inhibition. PDE4B has been proposed as a primary target by which PAN‐PDE4 inhibitors exert anti‐inflammatory effects. Here, we assessed whether genetic ablation of PDE4B is per se sufficient to protect mice infected with live P.aeruginosa from acute lung injury and whether PDE4B ablation can dampen immune responses without worsening the bacterial infection. Methods PDE4B knockout (PDE4BKO) mice and their wildtype (WT) littermates were infected intranasally with P.aeruginosa lab strain PA01 and bronchoalveolar lavage fluid (BALF) and lungs were harvested 16 h later to assess lung infection/inflammation. Results At 16 h post‐infection, the levels of pro‐inflammatory cytokines in BALF and lung tissue (TNFα, IL1β, IL‐6, and KC) as well as lung histopathological scores were reduced in PDE4BKO mice compared to their WT littermates indicating anti‐inflammatory benefits of PDE4B ablation, whereas the total number of leukocytes or neutrophils in BALF was unchanged. Unexpectedly, despite dampening the immune response, bacterial load in BALF and lungs was significantly decreased in PDE4BKO compared to WT controls. The ability of PDE4BKO mice to clear the bacteria more efficiently correlates with their ability to alleviate the significant PA ‐induced hypothermia observed in WT controls. Indeed, when differences in hypothermia between WT and PDE4BKO mice are equalized by externally warming the animals, the bacterial load in WT and KO mice are comparable whereas anti‐inflammatory benefits, such as reduced cytokines levels in PDE4BKO mice, are retained. Conclusions Our results suggest that ablation of PDE4B per se is sufficient to alleviate lung inflammation in a model of acute P.aeruginosa infection without worsening the bacterial infection. Thus, PDE4B may represent a therapeutic target for inflammatory lung diseases associated with P.aeruginosa infections, such as ventilator associated pneumonia or cystic fibrosis. Support or Funding Information Supported by grants from the Cystic Fibrosis Foundation (SALEH18H0, RICHTE16GO) and the NIH (HL76125, HL141473, HL066299).