title: Integrin αDβ2 (CD11d/CD18) mediates experimental malaria-associated acute respiratory distress syndrome (MA-ARDS).
abstract: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a potentially lethal complication of clinical malaria. Acute lung injury in MA-ARDS shares features with ARDS triggered by other causes, including alveolar inflammation and increased alveolar-capillary permeability, leading to leak of protein-rich pulmonary oedema fluid. Mechanisms and physiologic alterations in MA-ARDS can be examined in murine models of this syndrome. Integrin αDβ2 is a member of the leukocyte, or β2 (CD18), sub-family of integrins, and emerging observations indicate that it has important activities in leukocyte adhesion, accumulation and signalling. The goal was to perform analysis of the lungs of mice wild type C57Bl/6 (a D (+/+) ) and Knockout C57Bl/6 (a D (-/-) ) with malaria-associated acute lung injury to better determine the relevancy of the murine models and investigate the mechanism of disease.
  
  
  
  C57BL/6 wild type (a D (+/+) ) and deficient for CD11d sub-unit (a D (-/-) ) mice were monitored after infection with 10(5) Plasmodium berghei ANKA. CD11d subunit expression RNA was measured by real-time polymerase chain reaction, vascular barrier integrity by Evans blue dye (EBD) exclusion and cytokines by ELISA. Protein and leukocytes were measured in bronchoalveolar lavage fluid (BALF) samples. Tissue cellularity was measured by the point-counting technique, F4/80 and VCAM-1 expression by immunohistochemistry. Respiratory function was analysed by non-invasive BUXCO and mechanical ventilation.
  
  
  
  Alveolar inflammation, vascular and interstitial accumulation of monocytes and macrophages, and disrupted alveolar-capillary barrier function with exudation of protein-rich pulmonary oedema fluid were present in P. berghei-infected wild type mice and were improved in αDβ2-deficient animals. Key pro-inflammatory cytokines were also decreased in lung tissue from α D (-/-) mice, providing a mechanistic explanation for reduced alveolar-capillary inflammation and leak.
  
  
  
  The results indicate that αDβ2 is an important inflammatory effector molecule in P. berghei-induced MA-ARDS, and that leukocyte integrins regulate critical inflammatory and pathophysiologic events in this model of complicated malaria. Genetic deletion of integrin subunit αD in mice, leading to deficiency of integrin αDβ2, alters lung inflammation and acute lung injury in a mouse model of MA-ARDS caused by P. berghei.
authors.affiliation: Laboratório de Immunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, CEP 21045-900, Brazil. igomesdeazevedo@gmail.com.
authors.forename: Isaclaudia G
authors.initials: IG
authors.lastname: de Azevedo-Quintanilha
authors.affiliation: Program in Molecular Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. adrianav@u2m2.utah.edu.
authors.forename: Adriana
authors.initials: A
authors.lastname: Vieira-de-Abreu
authors.affiliation: Laboratório de Immunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, CEP 21045-900, Brazil.
authors.forename: André Costa
authors.initials: AC
authors.lastname: Ferreira
authors.affiliation: Laboratório de Immunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, CEP 21045-900, Brazil.
authors.forename: Daniele O
authors.initials: DO
authors.lastname: Nascimento
authors.affiliation: Laboratório de Immunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, CEP 21045-900, Brazil.
authors.forename: Alessandra M
authors.initials: AM
authors.lastname: Siqueira
authors.affiliation: Program in Molecular Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Campbell
authors.affiliation: Laboratório de Inflamação, Instituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Rio de Janeiro, Brazil.
authors.forename: Tatiana P
authors.initials: TP
authors.lastname: Teixeira Ferreira
authors.affiliation: Laboratório de Immunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, CEP 21045-900, Brazil.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Gutierrez
authors.affiliation: Laboratório de Engenharia Pulmonar no Programa de Engenharia Biomédica, Instituto Alberto Luiz Coimbra de Pós-Graduação e Pesquisa de Engenharia-COPPE/Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Ribeiro
authors.affiliation: Laboratório de Inflamação, Instituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Rio de Janeiro, Brazil.
authors.forename: Patricia M R
authors.initials: PM
authors.lastname: E Silva
authors.affiliation: Laboratório de Fisiologia da Respiração, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Carvalho
authors.affiliation: Laboratório de Immunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, CEP 21045-900, Brazil.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Bozza
authors.affiliation: Program in Molecular Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.affiliation: Laboratório de Immunofarmacologia, Instituto Oswaldo Cruz, Fiocruz, Pavilhão Ozório de Almeida, Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, CEP 21045-900, Brazil.|Programa de Produtividade Científica, Universidade Estácio de Sá, Rio de Janeiro, RJ, Brazil.
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Castro-Faria-Neto
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D018845:CD11 Antigens / Q000378:metabolism*; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005070:Evans Blue / Q000378:metabolism; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D039001:Integrin alpha Chains / Q000378:metabolism*; D007958:Leukocyte Count; D008168:Lung / Q000473:pathology; D008288:Malaria / Q000150:complications*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D010962:Plasmodium berghei / Q000254:growth & development; D011506:Proteins / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D012128:Respiratory Distress Syndrome / Q000473:pathology*; D012129:Respiratory Function Tests
chemical_list: D018845:CD11 Antigens; D016207:Cytokines; D039001:Integrin alpha Chains; D011506:Proteins; C527123:integrin alphaD, mouse; D005070:Evans Blue
keywords: Acute lung injury; Acute respiratory distress syndrome; Inflammation; Integrin αDβ2; Malaria