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individuals who refuse to quit smoking.63 Approximately 4000 substances in tobacco smoke have been

identified, and some have been shown to have a negative impact on healing.64 Most studies have

focused on the effects of nicotine, carbon monoxide, and hydrogen cyanide from smoke. Nicotine

interferes with oxygen supply by inducing tissue ischemia, since nicotine can cause decreased tissue

blood flow via vasoconstrictive effects.65 Nicotine stimulates sympathetic nervous activity, resulting in

the release of epinephrine, which causes peripheral vasoconstriction and decreased tissue blood

perfusion. Nicotine also increases blood viscosity caused by decreasing fibrinolytic activity and

augmentation of platelet adhesiveness. In addition to the effects of nicotine, carbon monoxide in

cigarette smoke also causes tissue hypoxia. Carbon monoxide binds to hemoglobin with an affinity 200

times greater than that of oxygen, resulting in a decreased fraction of oxygenated hemoglobin in the

bloodstream. Hydrogen cyanide, another well-studied component of cigarette smoke, impairs cellular

oxygen metabolism, leading to compromised oxygen consumption in the tissues. Beyond these direct

tissue effects, smoking increases the individual’s risk for atherosclerosis and chronic obstructive

pulmonary disease, two conditions that might also lower tissue oxygen tension.66

Several cell types and processes that are important to healing have been shown to be adversely

affected by tobacco smoke. In the inflammatory phase, smoking causes impaired white blood cell

migration, resulting in lower numbers of monocytes and macrophages in the wound site, and reduces

neutrophil bactericidal activity. Lymphocyte function, cytotoxicity of natural killer cells, and production

of IL-1 are all depressed, and macrophage sensing of gram-negative bacteria is inhibited.67 These effects

result in poor wound healing and an increased risk of opportunistic wound infection.

During the proliferative phase of wound healing, exposure to smoke yields decreased fibroblast

migration and proliferation, reduced wound contraction, hindered epithelial regeneration, decreased

ECM production, and upset in the balance of proteases.68

Pharmacologically, the influence of smoking on wound healing is complicated, and neither nicotine

alone nor any other single component can explain all of the effects of smoking on wounds. What is

certain is that smoking cessation leads to improved repair and reduces wound infection.69 For surgery

patients who find it difficult to forego smoking, the use of a transdermal patch during the preoperative

period might be beneficial. A study has shown that the use of a transdermal nicotine patch as a nicotine

replacement for smoking cessation therapy can increase type I collagen synthesis in wounds.70 Despite

the overall negative effects of smoking, some recent studies have suggested that low doses of nicotine

enhance angiogenesis and actually improve healing.71

Alcohol and Substance Abuse

Clinical evidence and animal experiments have shown that exposure to alcohol impairs wound healing

and increases the incidence of infection.72 The effect of alcohol on repair is quite clinically relevant,

since over half of all emergency room trauma cases involve either acute or chronic alcohol exposure.

Alcohol exposure diminishes host resistance, and ethanol intoxication at the time of injury is a risk

factor for increased susceptibility to infection in the wound.73 Studies have demonstrated profound

effects of alcohol on host-defense mechanisms, although the precise effects are dependent upon the

pattern of alcohol exposure (i.e., chronic vs. acute alcohol exposure, amount consumed, duration of

consumption, time from alcohol exposure, and alcohol withdrawal). A recent review on alcohol-induced

alterations on host defense after traumatic injury suggested that, in general, short-term acute alcohol

exposure results in suppressed pro-inflammatory cytokine release in response to an inflammatory

challenge. The higher rate of postinjury infection correlates with decreased neutrophil recruitment and

phagocytic function in acute alcohol exposure.74

Beyond the increased incidence of infection, exposure to ethanol also seems to influence the

proliferative phase of healing. In murine models, exposure to a single dose of alcohol that caused a

blood alcohol level of 100 mg/dL (just above the legal limit in most states in the United States)

perturbed re-epithelialization, angiogenesis, collagen production, and wound closure.75 The most

significant impairment seems to be in wound angiogenesis, which is reduced by up to 61% following a

single ethanol exposure. This decrease in angiogenic capacity involves both decreased expression of

VEGF receptors and reduced nuclear expression of HIF-1alpha in endothelial cells.76 The ethanolmediated decrease in wound vascularity causes increased wound hypoxia and oxidative stress.77

Connective tissue restoration is also influenced by acute ethanol exposure, and results in decreased

collagen production and alterations in the protease balance at the wound site. In summary, acute

ethanol exposure can lead to impaired wound healing by impairing the early inflammatory response,

inhibiting wound closure, angiogenesis, and collagen production, and altering the protease balance at

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the wound site.

As mentioned previously, the host response to chronic alcohol exposure appears to be different from

that of acute alcohol exposure. Analysis of clinical data indicates that chronic alcohol exposure causes

impaired wound healing and enhanced host susceptibility to infections, but the detailed mechanisms that

explain this effect need more investigation.

Cancer, Chemotherapy, and Radiation

Chemotherapeutic Drugs. Most chemotherapeutic drugs are designed to inhibit cellular metabolism,

rapid cell division, and angiogenesis and thus inhibit many of the pathways that are critical to

appropriate wound repair. These medications inhibit DNA, RNA, or protein synthesis, resulting in

decreased fibroplasia and neovascularization of wounds.78 Chemotherapeutic drugs delay cell migration

into the wound, decrease early wound matrix formation, lower collagen production, impair proliferation

of fibroblasts, and inhibit contraction of wounds.79 In addition, these agents weaken the immune

functions of the patients, and thereby impede the inflammatory phase of healing and increase the risk of

wound infection. Chemotherapy induces neutropenia, anemia, and thrombocytopenia, thus leaving

wounds vulnerable to infection, causing less oxygen delivery to the wound, and also making patients

vulnerable to excessive bleeding at the wound site.

Impaired wound healing due to chemotherapeutic drugs such as Adriamycin is most common when

the drugs are administered preoperatively or within 3 weeks postoperatively.80 Additionally, low

postoperative albumin levels, low postoperative hemoglobin, advanced stage of disease, and

electrosurgery use have all been reported as risk factors for the development of wound complications.81

A newer generation of tumor chemotherapeutics include angiogenesis inhibitors, such as

bevacizumab, which is an antibody fragment that neutralizes VEGF. These therapies work in conjunction

with traditional chemotherapeutics to limit the blood supply to tumors, reducing their ability to grow.

Wound healing complications, including an increase in wound dehiscence, have been described in

patients on angiogenesis inhibitors.82 A caveat is that most patients on angiogenesis inhibitors are also

on traditional chemotherapeutics, making it difficult to sort out whether angiogenesis inhibitors alone

would perturb repair.83 Nevertheless, current recommendations include discontinuation of angiogenesis

inhibitors well in advance of any surgical procedures.

Radiation

Radiation is one of the most commonly used therapies for the treatment of multiple types of human

cancer. It results in a wide range of acute and chronic toxicities, with poor health outcomes, and often

become dose-limiting for patients and impairing their quality of life (QoL) and recovery in both the

short and the long term.

4 Injury resulting from radiation and chemotherapy is initiated through two major paths: radiolytic

hydrolysis and stimulation of the innate immune response. Of the two, oxidative stress is the best

studied with respect to cancer treatment-associated tissue injury. After an initial exposure to radiation,

there is immediate damage to the keratinocyte cells of the skin, which is accompanied by a

simultaneous increase in free radicals, DNA damage, and inflammation. Radiation- or chemotherapyinduced oxidative stress leads to the production of oxygen free radicals; specifically the reactive oxygen

species superoxides, hydrogen peroxides, and hydroxyl radicals that cause oxidative damage to the

tissue. Inflammatory cells are recruited to the injured area, a process orchestrated by vasodilation and

vascular permeability. On the cellular level, fibrosis involves the coordination of a variety of cell types

largely mediated through the fibroblast. The infiltrating immune cells secrete cytokines that drive the

differentiation of fibroblasts and other self-renewing cells into myofibroblasts which deposit collagens

and other ECM proteins at and around the site of tissue damage.84

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