title: Granzyme A- and B-cluster deficiency delays acute lung injury in pneumovirus-infected mice.
abstract: Lower respiratory tract infection by the human pneumovirus respiratory syncytial virus is a frequent cause of acute lung injury in children. Severe pneumovirus disease in humans is associated with activation of the granzyme pathway by effector lymphocytes, which may promote pathology by exaggerating proapoptotic caspase activity and proinflammatory activity. The main goal of this study was to determine whether granzymes contribute to the development of acute lung injury in pneumovirus-infected mice. Granzyme-expressing mice and granzyme A- and B-cluster single- and double-knockout mice were inoculated with the rodent pneumovirus pneumonia virus of mice strain J3666, and were studied for markers of lung inflammation and injury. Expression of granzyme A and B is detected in effector lymphocytes in mouse lungs in response to pneumovirus infection. Mice deficient for granzyme A and the granzyme B cluster have unchanged virus titers in the lungs but show a significantly delayed clinical response to fatal pneumovirus infection, a feature that is associated with delayed neutrophil recruitment, diminished activation of caspase-3, and reduced lung permeability. We conclude that granzyme A- and B-cluster deficiency delays the acute progression of pneumovirus disease by reducing alveolar injury.
authors.affiliation: Pediatric Intensive Care Unit, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands. r.a.bem@amc.uva.nl
authors.forename: Reinout A
authors.initials: RA
authors.lastname: Bem
authors.forename: Job B M
authors.initials: JB
authors.lastname: van Woensel
authors.forename: Rene
authors.initials: R
authors.lastname: Lutter
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Domachowske
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.forename: Helene F
authors.initials: HF
authors.lastname: Rosenberg
authors.forename: Albert P
authors.initials: AP
authors.lastname: Bos
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D003603:Cytotoxins / Q000172:deficiency; D018450:Disease Progression; D053804:Granzymes / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D018111:Pneumovirus; D018186:Pneumovirus Infections / Q000150:complications*; D012141:Respiratory Tract Infections / Q000150:complications
chemical_list: D003603:Cytotoxins; D053804:Granzymes; D053148:Caspase 3