Role of the Fas/FasL system in a model of RSV infection in mechanically ventilated mice

Abstract

Infection with respiratory syncytial virus (RSV) in children can progress to respiratory distress and acute lung injury necessitating mechanical ventilation (MV). MV enhances apoptosis and inflammation in mice infected with pneumonia virus of mice (PVM), a mouse pneumovirus that has been used as a model for severe RSV infection in mice. We hypothesized that the Fas/Fas ligand (FasL) system, a dual proapoptotic/proinflammatory system involved in other forms of lung injury, is required for enhanced lung injury in mechanically ventilated mice infected with PVM. C57BL/6 mice and Fas-deficient ("lpr") mice were inoculated intratracheally with PVM. Seven or eight days after PVM inoculation, the mice were subjected to 4 h of MV (tidal volume 10 ml/kg, fraction of inspired O(2) = 0.21, and positive end-expiratory pressure = 3 cm H(2)O). Seven days after PVM inoculation, exposure to MV resulted in less severe injury in lpr mice than in C57BL/6 mice, as evidenced by decreased numbers of polymorphonuclear neutrophils in the bronchoalveolar lavage (BAL), and lower concentrations of the proinflammatory chemokines KC, macrophage inflammatory protein (MIP)-1α, and MIP-2 in the lungs. However, when PVM infection was allowed to progress one additional day, all of the lpr mice (7/7) died unexpectedly between 0.5 and 3.5 h after the onset of ventilation compared with three of the seven ventilated C57BL/6 mice. Parameters of lung injury were similar in nonventilated mice, as was the viral content in the lungs and other organs. Thus, the Fas/FasL system was partly required for the lung inflammatory response in ventilated mice infected with PVM, but attenuation of lung inflammation did not prevent subsequent mortality.

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

“…This includes a dysregulated recruitment of leukocytes and/or an exaggerated activation of these cells; inappropriate expression of cytokines, lipid mediators, or reactive oxygen species; enhanced activation of death receptor signaling (97,98,140,207,240); or an uncontrolled activity of platelets or the coagulation cascade (154). In general, these responses are initiated and maintained by recognition of danger-or pathogen-associated molecular patterns…”

“…This includes a dysregulated recruitment of leukocytes and/or an exaggerated activation of these cells; inappropriate expression of cytokines, lipid mediators, or reactive oxygen species; enhanced activation of death receptor signaling (97,98,140,207,240); or an uncontrolled activity of platelets or the coagulation cascade (154). In general, these responses are initiated and maintained by recognition of danger-or pathogen-associated molecular patterns (DAMPs/PAMPs) by highly conserved pattern recognition receptors such as TLRs (Toll-like receptors), NLRs (NOD-like receptors), RLRs (RIG-I-like receptors), C-type lectin receptors, and AIM2 (absence in melanoma 2-like) receptors (178,259,260).…”

The Pneumonia Virus of Mice (PVM) Model of Acute Respiratory Infection

“…In addition to increased levels of cytokines in the airways, mechanical ventilation activated caspase-dependent cell death pathways leading to acute lung injury in PVM-infected mice. In a subsequent study, van den Berg and colleagues [83] found that inflammatory injuries associated with mechanical ventilation were less severe in lpr (Fas-deficient) mice although all mice ultimately succumbed to infection.…”

Critical Adverse Impact of IL-6 in Acute Pneumovirus Infection

“…Among the individual cytokines with an impact on the pathogenesis of pneumovirus infection, CCL3 was shown to promote neutrophil recruitment; blockade of CCL3 or its receptor, CCR1, contributes improved survival in response to acute PVM infection (8,9). Other cytokine ligands and receptors implicated in promoting inflammatory pathology in PVM infection include cysteinyl leukotrienes, ChemR23, Fas/FasL, and CD8 + T cell-derived mediators (10)(11)(12)(13).…”