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In Vivo Assessment of Alveolar Macrophage Efferocytosis Following Ozone Exposure
Published on: October 22, 2019
Mechanisms for impaired effector function in alveolar macrophages from marijuana and cocaine smokers
Michael D Roth1, Katherine Whittaker, Ken Salehi
1Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Abstract:
Lung macrophages provide a first line of host defense against inhaled pathogens and their function is impaired in the lungs of inhaled substance abusers. In order to investigate the mechanism for this impairment, alveolar macrophages (AM) were recovered from nonsmokers (NS), regular tobacco smokers (TS), marijuana smokers (MS), or crack cocaine smokers (CS), and evaluated for their production of nitric oxide (NO) and the role of NO as an antimicrobial effector molecule. AM from NS and TS efficiently killed Staphylococcus aureus and their antibacterial activity correlated closely with the production of nitrite and the expression of mRNA encoding for inducible nitric oxide synthase (iNOS). In contrast, AM collected from MS and CS exhibited limited antimicrobial activity that was not affected by an inhibitor of iNOS, or associated with expression of iNOS. Treatment with either granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma restored the ability of these cells to produce NO and to kill bacteria. These findings confirm a significant role for NO as an antibacterial effector molecule used by normal human AM and suggest that this host defense mechanism is suppressed by habitual exposure to inhaled marijuana or crack cocaine in vivo.
Insights
Inhaled substance abuse, including marijuana and crack cocaine, impairs lung macrophage defense against bacteria by suppressing nitric oxide (NO) production. Restoring NO levels can revive the immune cells' ability to fight infection.
Area of Science:
- Immunology
- Infectious Disease
- Toxicology
Background:
- Lung macrophages are crucial for host defense against inhaled pathogens.
- Inhaled substance abuse impairs macrophage function, compromising lung immunity.
- Nitric oxide (NO) plays a role in the antimicrobial activity of alveolar macrophages.
Purpose of the Study:
- To investigate the mechanism of impaired lung macrophage function in users of inhaled substances.
- To evaluate the role of nitric oxide (NO) as an antimicrobial effector molecule in alveolar macrophages (AM) from different smoking groups.
- To determine if treatments can restore antimicrobial function in AM from substance abusers.
Main Methods:
- Alveolar macrophages (AM) were isolated from non-smokers (NS), tobacco smokers (TS), marijuana smokers (MS), and crack cocaine smokers (CS).
- Production of nitric oxide (NO) and nitrite, and expression of inducible nitric oxide synthase (iNOS) mRNA were measured.
- Antimicrobial activity against Staphylococcus aureus was assessed, with and without iNOS inhibition.
- AM function was evaluated after treatment with granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma.
Main Results:
- AM from NS and TS efficiently killed Staphylococcus aureus, correlating with NO production and iNOS expression.
- AM from MS and CS showed limited antimicrobial activity, independent of iNOS.
- Treatment with GM-CSF or interferon-gamma restored NO production and bacterial killing capacity in AM from MS and CS.
- These findings confirm NO's role as an antibacterial effector molecule in human AM.
Conclusions:
- Habitual exposure to inhaled marijuana or crack cocaine suppresses the nitric oxide-mediated antibacterial defense mechanism in human lung macrophages.
- Impaired nitric oxide production by alveolar macrophages in substance abusers compromises host defense against bacterial infections.
- Restoration of NO production through therapeutic interventions like GM-CSF or interferon-gamma can potentially revive antimicrobial functions.
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