Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages

HIV gp120 in the Lungs of Antiretroviral Therapy–treated Individuals Impairs Alveolar Macrophage Responses to Pneumococci

“…The failure of HIV-1BaL infected MDM to increase mROS production over baseline following pneumococcal challenge resulted in pneumococcal survival, similar to recent observations in AM from COPD patients (20). In contrast to the requirement for a late increment in mROS to achieve optimal intracellular killing, chronic baseline elevation of mROS, following HIV-1 or gp120 exposure, does not seem to enhance intracellular bacterial killing.…”

“…Caspase 3 activation promotes release of mROS by inhibiting the mitochondrial electron transport complex I and has been identified as a requirement for the increment of mROS generation that is required to mediate apoptosis-associated killing of intracellular pneumococci (20,27). The failure of HIV-1BaL infected MDM to increase mROS production over baseline following pneumococcal challenge resulted in pneumococcal survival, similar to recent observations in AM from COPD patients (20).…”

“…Consistent with this an inhibitor of mROS had no impact on early intracellular bacterial viability at 4 h. COPD AM also show chronic baseline elevation of intracellular mROS but no enhancement of early intracellular bacterial killing (20). To play a role in intracellular killing mROS needs to be generated in proximity to bacteria in phagolysosomes (20,28) and be produced at levels above baseline following caspase 3 activation to overwhelm anti-oxidant systems (20). In COPD there is not only reduced caspase 3/7 activation but also an altered balance between mROS generation and superoxide dismutase (SOD) 2 expression, which suggests increased ability to neutralize baseline mROS.…”

“…In contrast to the requirement for a late increment in mROS to achieve optimal intracellular killing, chronic baseline elevation of mROS, following HIV-1 or gp120 exposure, does not seem to enhance intracellular bacterial killing. Consistent with this an inhibitor of mROS had no impact on early intracellular bacterial viability at 4 h. COPD AM also show chronic baseline elevation of intracellular mROS but no enhancement of early intracellular bacterial killing (20). To play a role in intracellular killing mROS needs to be generated in proximity to bacteria in phagolysosomes (20,28) and be produced at levels above baseline following caspase 3 activation to overwhelm anti-oxidant systems (20).…”

“…Sample sizes were informed by standard errors obtained from similar assays in prior publications (10,20). Analysis was performed with tests, as outlined in the figure legends, using Prism 6.0 software (GraphPad Inc.) and significance defined as p<0.05.…”