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found that the lower BMD in smoker was dose dependent a higher number of neutrophils and macrophages in smokers,
(i.e., more smoking, lower BMD) and estimated a 40% and there appears to be smoking-related alterations in the func-
31% increase in the lifetime risk of hip fractures in male and tions of these cells. Neutrophil chemotaxis (movement to
female smokers, respectively. Smoking was associated with damaged tissue), migration within the wound, and phagocytic
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low BMD in British military recruits. There is also emerg- activity are impaired in smokers. 65,105,110–112 The macrophages
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ing evidence that long-term exposure to passive smoking of smokers have lower phagocytosis activity, lower responsive-
adversely effects BMD in a dose-dependent manner. With re- ness to bacterial challenge, impaired chemotaxis, and reduced
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gard to lifestyle, smokers generally have lower dietary intake gene expression of proinflammatory cytokines important for
of calcium and vitamin D. 78–81 Smoking also impairs intestinal tissue healing. 65,113–116
calcium absorption, 79,82,83 likely related to low serum calcitriol
(the metabolically active form of vitamin D that increases In the tissue proliferation phase, fibroblasts migrate to the site
calcium uptake from the gut) levels in smokers. 80,83 Smoking of the injury to synthesize and deposit a matrix composed of
also appears to effect osteogenesis. In rodents exposed to sec- collagen on which glycoproteins form. 65,117 Collagen deposi-
ond-hand smoke for 8 to 14 weeks, bone formation has been tion is the major factor that determines the tensile strength
shown to be inhibited. 84,85 When cigarette smoke or smokeless of healed wounds. 118,119 In cell preparations, cigarette smoke
tobacco is applied to bone cells, metabolic activity and prolif- extracts have been shown to reduce collagen content; decrease
eration of osteoblasts (bone cells that deposit new bone) are fibroblast recruitment, proliferation, migration, and contrac-
inhibited. 84,86,87 In contrast to cigarette smoke or tobacco, nico- tion; lead to delayed wound closure; and reduce the amount
tine (by itself) appears to act in a biphasic manner such that of new tissue formation. 120–123 Damage to the medial collateral
lower concentrations result in a proliferation of osteoblasts ligament resulted in less cellular density and reduced expres-
while higher concentrations decrease proliferation of these sion of Type I collagen in mice exposed to cigarette smoke for
cells and result in cellular death. 88,89 When nicotine receptors 2 months. Human studies involving experimentally induced
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are inhibited or nicotine removed from bone cells, the initial arm wounds showed that smokers produced less hydroxypro-
stimulatory effects are reduced suggesting that components in line, a marker of collagen production, 102,124 and synthesized
smoke other than nicotine may be involved in the effect on less Type I and Type III collagen. Noncollagen protein was
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osteoblasts. 86,87,89 With regard to sex hormones, estrogen in- apparently not affected. The metabolic pathway for col-
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creases osteoblastic activity but smoking has antiestrogenic lagen deficit in smokers may involve reduced conversion of
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and estrogen-lowering effects. 90,91 In summary, low BMD, proline to hydroxyproline, since this pathway requires molec-
lifestyle factors, and effects on calcium metabolism, osteogen- ular oxygen and smokers exhibit reduced tissue oxygenation
esis, and sex hormones provide possible mechanisms whereby (discussed later). Smoking attenuates epidermal healing in
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smoking increases the likelihood of fractures (Table 1). experimentally induced blisters and the epidermis of smok-
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ers is thinner 128
TABLE 1 Mechanisms Possibly Accounting for Influence of Smoking
on Risk of Fracture In summary, smoking (1) alters the functions of neutrophils
1. Low bone mineral density and monocytes, resulting in reduced ability to fight infections
2. Lifestyle factors and remove damaged tissue, (2) reduces the gene expression
a. Lower intake of calcium of cytokines important for tissue healing, and (3) affects fibro-
b. Lower intake of vitamin D blast function, leading to reduced density and amount of new
3. Calcium metabolism –Lower calcitriol levels reduce calcium tissue formation (Table 2).
absorption from the gut
4. Osteogenesis TABLE 2 Summary of Effects of Smoking on Wound Healing
a. Reduced bone formation
b. Reduced proliferation of osteoblasts 1. Inflammatory cell response
a. Neutrophils
3. Estrogen lowering effects reduce osteoblastic activity i. Increased number
ii. Reduced chemotaxis
Wound Healing iii. Reduced migration within wound
Wound healing can be simply divided into four major over- iv. Reduced bactericidal activity
lapping phases: hemostasis, inflammatory cell response, tissue b. Macrophages
proliferation, and maturation. In initial hemostasis phase, i. Increased number
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there is a cascade of events leading to the formation of a blood ii. Reduced chemotaxis
clot in the wound. In the second phase there is an infiltration iii. Lower phagocytosis activity
iv. Lower responsiveness to bacterial challenge
of inflammatory cells that begin the healing process. These v. Reduced gene expression of proinflammatory cytokines
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inflammatory cells include various types of white blood cells 2. Wound remodeling
(leukocytes) that control infection and assist in removal of a. Fibroblasts
damaged tissue. 93–96 Smoking increases the overall leukocyte i. Decreased recruitment
count in venous blood in a dose-dependent manner with smok- ii. Decreased proliferation
iii. Decreased migration
ing for a longer periods of time resulting in higher leukocyte b. Collagen
counts. 97–109 Important types of leukocytes for wound healing i. Reduced amount Type I
include neutrophils and monocytes/macrophages. Long before ii. Reduced amount of Type III
a wound occurs, monocytes enter the body tissues and swell
to become tissue macrophages that can remain in tissues for Vasoconstriction
months to years until needed. When a wound occurs, neutro- One of the acute effects of smoking is vasoconstriction and re-
phils and macrophages are attracted to the wound site and duced oxygen tension. Smoking a single cigarette reduced tis-
serve to control infection by phagocytosis and release of en- sue blood flow 12% to 36% 129,130 and reduced blood oxygen
zymes that assist in debridement of necrotic tissues. Despite tension by 10% to 48%. 129,131 The vasoconstriction appear to
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110 | JSOM Volume 18, Edition 1/Spring 2018