title: Inhibition of Phosphodiesterase-4 during Pneumococcal Pneumonia Reduces Inflammation and Lung Injury in Mice.
abstract: Pneumococcal pneumonia is a leading cause of mortality worldwide. The inflammatory response to bacteria is necessary to control infection, but it may also contribute to tissue damage. Phosphodiesterase-4 inhibitors, such as rolipram (ROL), effectively reduce inflammation. Here, we examined the impact of ROL in a pneumococcal pneumonia murine model. Mice were infected intranasally with 10(5)-10(6) CFU of Streptococcus pneumoniae, treated with ROL in a prophylactic or therapeutic schedule in combination, or not, with the antibiotic ceftriaxone. Inflammation and bacteria counts were assessed, and ex vivo phagocytosis assays were performed. ROL treatment during S. pneumoniae infection decreased neutrophil recruitment into lungs and airways and reduced lung injury. Prophylactic ROL treatment also decreased cytokine levels in the airways. Although modulation of inflammation by ROL ameliorated pneumonia, bacteria burden was not reduced. On the other hand, antibiotic therapy reduced bacteria without reducing neutrophil infiltration, cytokine level, or lung injury. Combined ROL and ceftriaxone treatment decreased lethality rates and was more efficient in reducing inflammation, by increasing proresolving protein annexin A1 (AnxA1) expression, and bacterial burden by enhancing phagocytosis. Lack of AnxA1 increased inflammation and lethality induced by pneumococcal infection. These data show that immunomodulatory effects of phosphodiesterase-4 inhibitors are useful during severe pneumococcal pneumonia and suggest their potential benefit as adjunctive therapy during infectious diseases.
authors.affiliation: 1 Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Luciana P
authors.initials: LP
authors.lastname: Tavares
authors.affiliation: 2 Laboratório de Vírus Respiratórios e do Sarampo, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Cristiana C
authors.initials: CC
authors.lastname: Garcia
authors.affiliation: 1 Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.|3 Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.|4 Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Juliana P
authors.initials: JP
authors.lastname: Vago
authors.affiliation: 4 Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Celso M
authors.initials: CM
authors.lastname: Queiroz-Junior
authors.affiliation: 1 Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Izabela
authors.initials: I
authors.lastname: Galvão
authors.affiliation: 4 Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Bruna A
authors.initials: BA
authors.lastname: David
authors.affiliation: 5 Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Milene A
authors.initials: MA
authors.lastname: Rachid
authors.affiliation: 6 Laboratório de Inflamação, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil and.
authors.forename: Patrícia M R
authors.initials: PM
authors.lastname: Silva
authors.affiliation: 1 Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.|7 Laboratório de Imunologia e Mecânica Pulmonar, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Remo C
authors.initials: RC
authors.lastname: Russo
authors.affiliation: 1 Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: 1 Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.|3 Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.|4 Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Lirlândia P
authors.initials: LP
authors.lastname: Sousa
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D055370:Lung Injury / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D010587:Phagocytosis / Q000187:drug effects; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011014:Pneumonia / Q000150:complications* / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011018:Pneumonia, Pneumococcal / Q000150:complications* / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D012129:Respiratory Function Tests; D020889:Rolipram / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000502:physiology
chemical_list: D017305:Annexin A1; D000900:Anti-Bacterial Agents; D058988:Phosphodiesterase 4 Inhibitors; D002443:Ceftriaxone; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram
keywords: Annexin A1; Streptococcus pneumoniae; immunomodulation; inflammation; phosphodiesterase-4