Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice.
BACKGROUND
Cigarette smoke has both pro-inflammatory and immunosuppressive effects. Both active and passive cigarette smoke exposure are linked to an increased incidence and severity of respiratory virus infections, but underlying mechanisms are not well defined. We hypothesized, based on prior gene expression profiling studies, that upregulation of pro-inflammatory mediators by short term smoke exposure would be protective against a subsequent influenza infection.


METHODS
BALB/c mice were subjected to whole body smoke exposure with 9 cigarettes/day for 4 days. Mice were then infected with influenza A (H3N1, Mem71 strain), and analyzed 3 and 10 days later (d3, d10). These time points are the peak and resolution (respectively) of influenza infection.


RESULTS
Inflammatory cell influx into the bronchoalveolar lavage (BALF), inflammatory mediators, proteases, histopathology, viral titres and T lymphocyte profiles were analyzed. Compared to smoke or influenza alone, mice exposed to smoke and then influenza had more macrophages, neutrophils and total lymphocytes in BALF at d3, more macrophages in BALF at d10, lower net gelatinase activity and increased activity of tissue inhibitor of metalloprotease-1 in BALF at d3, altered profiles of key cytokines and CD4+ and CD8+ T lymphocytes, worse lung pathology and more virus-specific, activated CD8+ T lymphocytes in BALF. Mice smoke exposed before influenza infection had close to 10-fold higher lung virus titres at d3 than influenza alone mice, although all mice had cleared virus by d10, regardless of smoke exposure. Smoke exposure caused temporary weight loss and when smoking ceased after viral infection, smoke and influenza mice regained significantly less weight than smoke alone mice.


CONCLUSIONS
Smoke induced inflammation does not protect against influenza infection.In most respects, smoke exposure worsened the host response to influenza. This animal model may be useful in studying how smoke worsens respiratory viral infections.
Gualano
Rosa C
RC
Department of Pharmacology, The University of Melbourne, Parkville 3010, Victoria, Australia. rgualano@unimelb.edu.au
Hansen
Michelle J
MJ
Vlahos
Ross
R
Jones
Jessica E
JE
Park-Jones
Ruth A
RA
Deliyannis
Georgia
G
Turner
Stephen J
SJ
Duca
Karen A
KA
Anderson
Gary P
GP
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D004195:Disease Models, Animal; D007165:Immunosuppression Therapy; D009980:Influenza A virus / Q000276:immunology / Q000472:pathogenicity; D008168:Lung / Q000201:enzymology / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000473:pathology; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D010447:Peptide Hydrolases / Q000378:metabolism; D011014:Pneumonia / Q000473:pathology / Q000503:physiopathology* / Q000821:virology*; D012907:Smoking / Q000009:adverse effects*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D019714:Tissue Inhibitor of Metalloproteinases; D010447:Peptide Hydrolases