Effects of Cigarette Smoke on The Immune System

Effects of Cigarette Smoke on The Immune System Chiung-Zuei Chen MD Department of Internal Medicine National Cheng Kung University Hospital

n n Cigarette Smoking and Infection Effects of Cigarette Smoke on The Immune System Macrophage and Innate Immunity- Scavenger Receptor MARCO The Effects of Cigarette Smoke Extract on MARCO Expression and Mp clearance by THP-1 Cells

Cigarette Smoking and Infection Cigarette Smoking and Invasive Pneumococcal Disease n Population-based Case-Control study Healthy young and middle-aged adults 18~64 years of age 228 patients vs 301 control n N Engl J Med 2000; 342: 681 -9

Cigarette Smoking and Infection n Independent Risk Factors for Invasive Pneumococcal Disease among Immunocompetent Adults 18 to 64 Years Old Variable ODDs Ratio P value Male 2. 7(1. 7 -4. 3) <0. 001 Black Race 3. 4(2. 0 -5. 6) <0. 001 Chronic illness 2. 6(1. 4 -5. 1) 0. 005 Current Smoker 4. 1(2. 4 -7. 3) <0. 001 Passive exposure 2. 5(1. 2 -5. 1) 0. 01 Children household 3. 0(1. 5 -6. 2) 0. 003 Smoking status N Engl J Med 2000; 342: 681 -9

Cigarette Smoking and Infection n Dose-Response Relations N Engl J Med 2000; 342: 681 -9 Variable ODDs Ratio P value No. of cigarette smoked reference Adjusted for multiple variables 1 -14/day 2. 3(1. 3 -4. 3) 0. 006 15 -24/day 3. 7(1. 8 -7. 8) <0. 001 >25/day 5. 5(2. 5 -12. 9) <0. 001

Cigarette Smoking and Infection Cigarette Smoking as a Risk Factor for Epidemic A(H 1 N 1) Influenza in Young Men n 336 healthy young male recruits in the Israeli military unit n Incidence 68% (smoker) vs 47. 2% (Non-smoker) OR: 2. 42 (1. 53 -3. 83) p<0. 001 N Engl J Med 1982; 307: 1042 -6

Cigarette Smoking and Infection Rate of severe Influenza Light-smoker (up to 10/day) Moderate (11 -20/day) Heavy-smoker (>20/day) No(%) ODDs Ratio Nonsmoker 49(30. 1) 1. 00 Light. Smoker 15(42. 9) 1. 74 Moderate 32(51. 6) 2. 48 -Smoker N Engl J Med 1982; 307: 1042 -6 Heavy. Smoker 38(53. 5) 2. 68

Cigarette Smoking and Infection Smoking and Mortality from Tuberculosis and Other Disease in India n Large case-control study/ Mortality at age 2569 years n Retrospective study of 43000 adult male death and 35000 controls Lancet 2003; 362: 507 -15

Cigarette Smoking and Infection Smoking and Mortality from Tuberculosis and Other Disease in India n Prevalence risk ratio of tuberculosis was 2. 9(2. 6 -3. 3) for ever-smokers vs never smokers n Risk ratio of tuberculosis death was for ever-smokers vs never smokers 4. 5 (4. 0 -4. 5) and 4. 2(3. 7 -4. 8) for urban & rural residents Lancet 2003; 362: 507 -15

Effects of Cigarette Smoke on the Immune System Impact of Cigarette Smoke on Clearance and Inflammation after Pseudomonas aeruginosa Infection n C 57 BL/6 Mice n 1 R 1 or 1 R 3 reference cigarette daily (5 days per week for 6 -8 weeks) Am J Respir Crit Care 2004; 170: 1164 -1171

Impact of Cigarette Smoke on Clearance and Inflammation after Pseudomonas aeruginosa Infection Delayed rate of bacterial clearance after 4 & 12 Hrs bacterial inoculation in smoke-exposed for 68 weeks mice * P<0. 05 n * * * Am J Respir Crit Care 2004; 170: 1164 -1171

Immunotoxicology of Cigarette Smoke Condensates: Suppression of Macrophage Responsiveness to Interferon γ C 57 BL/6 mice treat with CSC-MS n Short-term exposure culture murine peritoneal macrophages as a model n Toxicol Appl Pharmacol 1998; 149: 136 -143

Immunotoxicology of Cigarette Smoke Condensates: Suppression of Macrophage Responsiveness to Interferon γ n CSC-MS inhibited increase in phagocytosis in response to Interferon -γover 18 Hrs % phagocytosis 35 35 [CSC-MS]% 0 0. 04 0. 06 30 25 20 0. 08 0. 1 Toxicol Appl Pharmacol 1998; 149: 136143

Immunotoxicology of Cigarette Smoke Condensates: Suppression of Macrophage Responsiveness to Interferon -γ n CSC-MS enhanced TNF -α production in response to LPS over 18 Hrs (0 vs 0. 05 vs 0. 1% CSC-MS) 0 Toxicol Appl Pharmacol 1998; 149: 136 -143

Cigarette Smoke & Phagocyte Function: Effect of Chronic Exposure in Vivo & Acute Exposure in Vitro n Phagocytosis Activity (30 Minutes & 24 Hours) 100. 0+2. 1 (control) vs 21. 8+0. 96 (smoke) p<0. 05 100. 0+4. 0 (control) vs 28. 6+3. 5 (smoke) p<0. 05 Infection & Immunity 1978; 20: 468 -475

Macrophage & Innate Immunity n n 1. 2. A first line of defense against microbial invaders To distinguish dangerous non-self materials from self-molecules; Pattern Recognition Receptors Non-phagocytic : Toll-like receptor Phagocytic : Scavenger receptor

Macrophage & Innate Immunity n n 1. 2. 3. MARCO MAcrophage Scavenger Receptor with COllagenous Structure SR-A Restricted to subpopulations of macrophage Bind a range of G(-) & G(+) bacterial & environmental particles

MAcrophage Scavenger Receptor with COllagenous structure

The Scavenger Receptor MARCO is Required for Lung Defense against Pneumococcal pneumonia & Inhaled Particles n n MARCO-/- vs C 57 BL/6 wild type mice Intranasal instillation Pneumococcal pneumonia 4 & 24 Hrs J Exp Med 2004; 200: 267 -272

The Scavenger Receptor MARCO is Required for Lung Defense against Pneumococcal pneumonia & Inhaled Particles n n MARCO-/- mice displaced an impaired ability to clear bacteria from the lungs ~8% (MARCO+/+) vs >50% (MARCO-/-) J Exp Med 2004; 200: 267 -272

The Scavenger Receptor MARCO is Required for Lung Defense against Pneumococcal pneumonia & Inhaled Particles MARCO-/- mice increased pulmonary inflammation & cytokine release More neutrophils 17+7. 40 (MARCO-/-) vs 2. 45+0. 46% (MARCO+/+) n TNF-α & MIP-2 0. 58+0. 14 (MARCO-/-) vs 0. 13+0. 01 (MARCO+/+) n J Exp Med 2004; 200: 267 -272

The Scavenger Receptor MARCO is Required for Lung Defense against Pneumococcal pneumonia & Inhaled Particles MARCO-/- mice diminished survival Mortality: 100% (MARCO-/-) vs 40% (MARCO+/+) n n In vitro phagocytosis ability was dramatically impaired J Exp Med 2004; 200: 267 -272

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages Introduction (I) n Mycoplasma pneunoniae (Mp) plays an important role in the acute exacerbation of COPD n Lung macrophages are the first line of defense against infection or inhaled agents

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages Introduction (II) n Acute exposure to cigarette smoke (CS) has been shown to inhibit the bactercidal activity of alveolar macrophage for Pseudomonas aeruginosa n The mechanisms involved in CS-induced inhibition of macrophage phagocytosis are still unknown

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages Introduction (III) n MARCO contributes to macrophage phagocytosis of typical bacteria Hypothesis n We hypothesize that CS decreases macrophage’s MARCO expression thus impairing phagocytosis of bacteria (e. g. Mp)

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages Methods n Human THP-1 derived macrophages were used as a model to test the effect of acute (6 Hr) CSE exposure (5%, 10% and 20%) on MARCO m. RNA (Real Time RT-PCR) and Protein (Western Blotting) expression (n=5)

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages 30+11% (p=0. 06) 36+8% (p=0. 01) 46+13% (p=0. 03)

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages Methods n The effects of MARCO on Mp clearance by macrophages were assessed (n=3) n After a 6 Hr CSE, macrophages were infected with Mp (1 CFU/cell) for 2 Hrs n Supernatants and monolayer of macrophages were collectede for total Mp counting

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages A 6 Hr exposure 20% CSE increased total Mp count by 27% 74+0. 6 vs 58+2. 2 10000 CFU/ml P=0. 046

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages Methods n The effects of MARCO on Mp clearance by macrophages were tested using a MARCOneutralizing Ab (0. 002, 0. 02 and 0. 2 μg/ml) at 1 Hr prior to Mp (1 CFU/cell) n=4

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages 17+4. 9% (p=0. 07) 29+4. 9% (p=0. 03) 30+2. 1% (p=0. 005)

The Effects of CSE on MARCO Expression and Mp Clearance by Human THP-1 derived Macrophages Conclusion n Acute exposure of CSE caused a reduction of MARCO expression and Mp clearance by macrophages n CSE-induced reduction of Mp clearance by macrophages may be partially through the down-regulation of MARCO expression

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