Re: What are the pathophysiological responds due to smoking?

Nicotine maintains tobacco addiction. Nicotine acts on nicotinic cholinergic receptors, in the nervous system, mediating the multiple actions of nicotine described in 
tobacco users. Nicotine addiction is more prevalent and more severe in people with a history of major depression, schizophrenia, or alcohol or other drug abuse problems. 
The cigarette is a highly efficient drug delivery system, delivering nicotine rapidly and in relatively high concentrations to the brain, a situation that optimizes the likelihood 
of self-administration. 
Lung cancer is the most frequent cancer worldwide, accounting for about 12% of all new cancer diagnoses in the two sexes combined. During the 1950s and 1960s clear 
evidence emerged that smoking was the cause of striking lung cancer increases. Risk of lung cancer increases approximately with the fourth power of duration of 
smoking and the square of the number of cigarettes smoked daily. Between 1990 and 1994, lung cancer mortality rates showed first decreases in the US and several 
European countries, including Italy, in men although not in women. Marked shifts are, however, taking place in the incidence of different types of cancer which had 
always been the predominant type in women and non-smokers, is increasingly associated with tobacco smoking. Since the 1950s steady rises in the incidence of cancer of 
the lung have been observed in many developed countries. Increases are similar in the two sexes and have followed a clear cohort pattern, paralleling changes in smoking 
habits and cigarette design more than diagnostic advances. Low-yield filter cigarettes tend to be inhaled more deeply than high-yield cigarettes in order to satisfy a craving 
for nicotine. The peripheral part of the lung, where most adenocarcinomas arise, is thus exposed to a disproportionately higher amount of smoke carcinogens. The hazards 
of light and ultra-light cigarettes tend to be underestimated, whereas the only safe cigarette is the non-smoked one.
Cigarette smoking is the largest preventable risk factor for morbidity and mortality in developed countries. Dramatic changes in the prevalence of cigarette smoking in the 
second half of this century in the United States (i.e., a reduction among men and an increase among women) have reduced current smoking levels to approximately one 
quarter of the adult population and have reduced differences in smoking prevalence and smoking-attributable diseases between the sexes. Nicotine dependence is the single 
most common psychiatric diagnosis in the United States, and substance abuse, major depression, and anxiety disorders are the most prevalent psychiatric comorbid 
conditions associated with nicotine dependence. Studies in twins have implicated genetic factors that explain most of the variability in vulnerability to smoking and in 
persistence of the smoking phenotype.
Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality in developed countries. Epidemiologic evidence links cigarette smoking with coronary 
artery disease. However, these epidemiologic data are derived from studies in smokers, and so may be colored by the effects of carbon monoxide and other components of 
tobacco smoke. In addition, the mechanism(s) for this linkage is (are) obscure. Furthermore, there is a widespread belief that cessation of smoking, via nicotine use in 
other forms (gum, snuff, etc.), may improve coronary risk. Sustained nicotine exposure leads to increased coronary risk by worsening these risk factors Short-term 
nicotine exposure results in significant increase in blood pressure, but no deterioration in glucose tolerance or insulin action, addressed by oral glucose tolerance testing.. 
Experiments are now under way to evaluate any changes in enzymes involved in cardiac intermediary metabolism, given that heart weight increase commensurate with the 
observed increase in blood pressure in animals treated with nicotine. 
Cigarette smoking is well recognized to be the most preventable cause of cardiovascular morbidity and mortality. A wealth of studies have documented an excess death 
rate from coronary artery disease in smokers as well as an increased risk of sudden death. However the mechanisms relating to this excess cardiovascular morbidity and 
mortality remain poorly understood. A number of possible mechanisms have been investigated including enhanced platelet activation, elevated fibrinogen, WBC and RBC 
levels, and increased oxidative stress. In addition, a number of studies have demonstrated abnormal lipid levels compared to normal people.
Smoking following overnight abstention reliably increases heart rate (HR), an effect due to nicotine absorption. The effect of subsequent cigarettes on HR is less than that 
associated with the first cigarette of the day, an indication of tachyphylaxis (acute tolerance). To date, smoking/HR studies have not been conducted double-blind. Instead, 
control conditions have included non-smoking or some type of "sham" smoking (puffing on an unlit cigarette or a straw). Objective: Smoking increases heart rate directly 
and thus predisposes to the development of arrhythmia’s. Ambulatory 24-h blood pressure monitoring was conducted in 135 healthy, normotensive, middle-aged (35 to 60 
years) men, with no antihypertensive medication, to study the influence of habitual smokeless tobacco use (n = 47) and smoking (n = 29) on diurnal blood pressure and 
heart rate. Comparisons were made with nonusers of tobacco (n = 59). Adjustments were made for differences in age, body mass index, waist-hip ratio, physical fitness, 
and alcohol intake. Daytime ambulatory heart rates were significantly (P < .05) elevated in both smokeless tobacco users and smokers compared with nonusers (69 +/- 14 
and 74 +/- 13 beats/min, respectively, versus 63 +/- 12 beats/min). In subjects > or = 45 years old, ambulatory daytime diastolic blood pressures were significantly 
elevated, on average by 5 mm Hg, in both smokeless tobacco users and smokers (P < .001) compared with nonusers. Clinical measurements of heart rate and systolic 
blood pressure in smokers were significantly lower compared with the ambulatory mean values. Nighttime measurements showed only minor differences between the 
tobacco habit groups. The higher heart rates and blood pressures noted during the daytime in smokers and smokeless tobacco users were most likely due to the effects of 
nicotine. A strong positive relationship was found between cotinine (major nicotine metabolite) and blood pressure in smokeless tobacco users , diastolic blood pressure, 
whereas an inverse relationship was found in smokers indicating additional and more complex influences on vascular tone in smokers than the influence of nicotine in 
smokeless tobacco users.
The use of transdermal nicotine patches increases the risk for acute myocardial infarction (heart attack, AMI) and f the combination of nicotine patch use and concomitant 
smoking is a risk factor of AMI. 
Accumulation of monocytes and neutrophils and fibrous distortion of the airway are characteristics of airway disease secondary to smoking. The presence of 
inflammatory cells and fibrosis correlate, and, therefore, we postulated that lung fibroblasts might release chemotactic activity for neutrophils and monocytes in response 
to smoke extract. To test this hypothesis, human fetal lung (HFL1) fibroblasts were cultured, and the supernatant fluid was evaluated for neutrophil (NCA) and monocyte 
(MCA) chemotactic activities with a blind well chamber technique. HFL1 fibroblasts released chemotactic activity in response to smoke extract in a dose- and time-
dependent manner. Checkerboard analysis showed that the activity was predominantly chemotactic. Partial characterization of the released chemotactic activity revealed 
that the activity was partly heat labile, trypsin sensitive, and ethyl acetate extractable. Lipoxygenase inhibitors and cycloheximide inhibited the release of both NCA and 
MCA. Molecular-sieve chromatography revealed that NCA and MCA were heterogeneous. NCA was inhibited by anti-human interleukin (IL)-8 and anti-granulocyte 
colony-stimulating factor antibodies and a leukotriene (LT) B(4)-receptor antagonist. Anti- granulocyte-macrophage colony-stimulating factor (GM-CSF) and anti- 
monocyte chemoattractant protein (MCP)-1 antibodies and an LTB(4)- receptor antagonist inhibited MCA. Immunoreactive IL-8, granulocyte colony-stimulating factor, 
GM-CSF, and MCP-1 significantly increased in culture supernatant fluid in response to smoke extract. Finally, smoke extract augmented the expression of mRNAs of IL-
8, GM-CSF, and MCP-1. These data demonstrate that lung fibroblasts release NCA and MCA in response to smoke extract and suggest that lung fibroblasts may modulate 
the inflammatory cell recruitment into the lung. 
The characteristics of this inflammatory process differ between smokers who develop chronic airflow limitation (COPD) and those who do not develop chronic airflow 
limitation: there is an increased infiltration of CD8-positive T lymphocytes in smokers with COPD. When the disease becomes severe, a prominent neutrophilia occurs. The 
precise roles of the CD8(+) T lymphocyte and the neutrophil in the pathogenesis of COPD still remain to be determined.

Salik Jahania  (salik@home.com)