Nicotine and Inflammatory Disease in Humans: A Systematic Review

The mechanisms behind the pro-inflammatory response to nicotine are thought to arise from stimulation of the sympathetic nervous system. Simplistically, nicotine binds to nicotinic acetylcholinergic receptors (nAChRs) on sympathetic nerve cells, leading to increased noradrenaline (9), stimulation of β3 adrenergic receptors, and release of hematopoietic stem and progenitor cells from bone marrow niches (10). These in turn differentiate into monocytes, which infiltrate sites of existing inflammation and recruit further immune cells, perpetuating chronic inflammation.

Anti-inflammatory mechanisms in response to nicotine are thought to arise through the direct interaction of nicotine with nAChRs on the surface of immune regulatory cells. The α7 sub-type of nAChRs is expressed on a variety of immune cells such as B cells, eosinophils, dendritic cells, monocytes, macrophages, T cells and neutrophils, with the inflammatory response specific to each cell type (8). Nicotine binding to the receptor brings about a conformational change to the receptor structure, opening of ion gated channels and the subsequent flux of calcium, potassium and sodium. This leads to reduced inflammatory cytokine release through the JAK/STAT pathway (the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating the immune system), as well as decreased NF-κB signaling and a reduction in TNF-α production (7).

Although the proposed pro- and anti-inflammatory mechanisms have been demonstrated in animal and cell models, the effects of nicotine in humans are less clear. The aim of this study was to carry out a systematic review of publications investigating the inflammatory effects of nicotine in models of human disease.

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklists were followed during the design and implementation of this study (Supplementary File 1) (11). Meta-analyses were not conducted. The prevalence of studies with small sample size, the heterogeneity of the reported study designs and the range of inflammatory disorders covered precluded the use of meta-analyses. PubMed, Science Direct and the Cochrane Library databases were searched using the strategies outlined in Table 1. Initial searches were carried out on 5^th April 2021. No time restrictions were applied with respect to article inclusion. No restrictions were applied with respect to the quality of the articles included in this review. Reference lists of relevant review articles were screened for additional original articles that did not appear in the searches. JTI internal databases were also searched. A subsequent database screen from 5th April 2021 – 19th November 2021 was carried out to make sure the most up-to-date publications were included before submission.

Articles were considered for inclusion in this review if they were:

Published in English;

Articles were excluded from this review if they were:

Published in any language other than English;

The 19 studies reviewed in this section are listed in Supplementary File 3.

The six studies reviewed in this section are listed in Supplementary File 3.

The acute effects of nicotine on vascular function have been extensively investigated, whereby the mechanisms predominantly manifest through stimulation of the sympathetic nervous system and activation of the hypophysis adrenal axis leading to increased plasma levels of adrenocorticotropic hormone (ACH), cortisol and adrenaline (39). The development of atherosclerosis, however, is a chronic process. Although definitive pathways relating nicotine to atherosclerosis have not been established, one proposed mechanism is through the recruitment of inflammatory cells via release of adhesion molecules (6). Evidence for this mechanism has been extensively provided though in vitro and in vivo animal models, however, human studies are rare. In all of the published studies, current smokers were recruited to take part, making it necessary to interpret all results with caution. One example is a placebo-controlled trial which investigated circulating adhesion molecules in healthy smokers after quitting with high dose transdermal nicotine patch or a placebo patch. After cigarette cessation, a dramatic decline in circulating soluble intracellular adhesion molecule-1 (sICAM-1), soluble CD44 splice variants sCD44v5 and sCD44v6 levels were observed, with no difference between those receiving nicotine patches and those receiving sham patches. The authors concluded “as NRT did not influence the rapid decline in soluble adhesion molecule concentrations, this study provides strong in vivo evidence that it is a constituent(s) of tobacco smoke other than nicotine, or its metabolites, that is responsible for the elevated sICAM-1, sCD44v5 and sCD44v6 concentrations noted in habitual smokers” (40).

Mobarrez et al. investigated the effect of acute exposure to nicotine-containing and nicotine-free e-cigarette vapor in 15 young healthy occasional smokers. Participants were required to abstain from any nicotine intake for two weeks prior to the trial, which was confirmed by biochemical testing. Four hours after 30 puffs of 3 s duration, an increase in extracellular vesicles derived from endothelial cells were observed. No increase was found when nicotine-free e-liquid was inhaled. Extracellular vesicles are known to have a variety of functions, including regulation of the inflammatory response; however, other than knowing the cell type of origin, this study did not allow any indication of the function(s) of the extracellular vesicles produced. The authors also acknowledged that the cigarette consumption of the participants may have influenced the results and the small number of participants means that the outcomes should be interpreted cautiously (41).

In another study in 23 young, healthy smokers, 24 h smoking abstinence with nicotine replacement therapy (NRT) did not result in a change to markers of inflammation such as C-reactive protein, monocyte chemo-attractant protein-1 (MCP-1), soluble intracellular adhesion molecule-1 (sICAM-1) or myeloperoxidase (MPO), or changes in flow mediated dilation (FMD). Co-administration of nicotine replacement therapy and γ-tocopherol-rich mixture of tocopherols (antioxidants) resulted in a significant decrease in FMD, suggesting that the mechanism was driven by oxidative stress, rather than inflammation in this study. The authors suggest that smokers who quit using NRT may limit any improvement of vascular endothelial function (42).

Contrary to this finding, serum levels of the inflammatory markers sICAM-1 and interleukin (IL)-1β decreased after three months when healthy male smokers transitioned to nicotine patches. Improvements were found in arterial stiffness; however, no change was observed in endothelial function. The authors concluded “these findings indicated that NRT-assisted smoking cessation might have important beneficial effects in vascular function by the way of reducing the inflammatory process”; however, it is not clear whether the improvement observed was due to nicotine or whether the reduction in the inflammatory effect of smoking led these changes (43).

A randomized, double-blinded, crossover trial in 17 healthy occasional users of tobacco products was carried out to investigate acute vascular and pulmonary effects of nicotine-containing e-liquids. After 30 puffs of an e-cigarette containing either nicotine or no nicotine, no difference was found in the exhaled marker of pulmonary inflammation, fractional exhaled nitric oxide. Although acute vascular response was measured, markers of vascular inflammation were not (44). These results repeated a finding from a previous study from the same group, where there was no difference in fractional exhaled nitric oxide or serum inflammatory-associated micro-vesicles found after 10 puffs of an e-cigarette containing nicotine. In this previous clinical trial, the authors did find a significant increase in endothelial progenitor cells (EPC) circulating after e-cigarette exposure; however, it is unclear if this increase related to an inflammatory response (45). In fact, the premise that increased circulating EPC levels indicated a pathological response was challenged by a letter to the editor pointing out that a reduction in circulating EPCs is usually associated with chronic diseases such as hyperlipidemia, hypertension, obesity and diabetes. Longer term interventions such as exercise and green tea consumption have also been shown to increase circulating EPCs (46). Overall, the relationship between EPC release into the bloodstream and inflammation or atherosclerosis is far from clear, especially considering the differences in acute and chronic responses (47).

The five studies reviewed in this section are summarized in Supplementary File 3.

In a small study of ten participants, nicotine patches were applied before the skin was exposed to different irritants. The authors found that nicotine suppressed the inflammatory response to topical sodium lauryl sulphate and UV-B irradiation. No difference in cutaneous blood flow was observed (48). The authors point out that despite the therapeutic potential of transdermal nicotine in the context of inflammatory skin conditions, application in non-smokers could be limited due to the adverse events typically experienced in those not desensitized to nicotine.

A Japanese medical team demonstrated that transdermal nicotine patches were effective in the treatment of eosinophilic pustular folliculitis. Of the eight patients recruited, six showed significant clinical improvement; two were unchanged (49).

A systematic review highlighted six studies where smokers were randomized either to receive transdermal nicotine patches or complete nicotine abstinence post wound infliction (either surgical or as a controlled procedure). Different wound healing mechanisms seemed to be affected both positively and negatively in the studies, making overall interpretation difficult. The authors concluded that “nicotine appears to attenuate inflammatory wound healing mechanisms, compared to proliferative wound healing mechanisms including angiogenesis and collagen synthesis. Clinically, there is no evidence to suggest that nicotine administered as nicotine replacement drugs to abstinent smokers has a detrimental or beneficial effect on postoperative outcome of wound or tissue healing”. Smoking status was a significant confounder in these studies and could have led to the inconclusive result (50).

The four studies reviewed in this section are listed in Supplementary File 3.

Twenty healthy non-smokers were randomized and blinded to receive either a nicotine patch or a placebo patch during their recovery from third molar tooth removal. During the post-operative period, the participants who had received the nicotine patches were administered significantly fewer analgesic tablets compared to the placebo control group (mean 2.35 vs. 4.35, respectively; p = 0.026) and rated their recovery as more satisfactory than those who received the placebo. Swelling was also reduced during the first 72 h post-surgery, indicating an anti-inflammatory effect in the patients who received the nicotine patch (53). The authors suggest that the nicotine patch is the most effective mode of administration as peak plasma concentration occurs at around the same time as peak post-operative pain and initiation of the inflammatory response.

Infection with gram negative bacteria, such as E. coli and Salmonella induces a strong immune response via interaction of lipopolysaccharides (LPS) on the bacterial outer membranes with various immune cells such as monocytes and macrophages, leading to release of pro-inflammatory cytokines. In a small study, 11 healthy, young male volunteers were exposed to intravenous LPS whilst wearing a nicotine patch or a placebo dressing. After LPS administration, the authors showed that all participants had similar increased concentrations of plasma inflammatory cytokines TNF-α, IL-6 and IL-8; however, those participants who were pre-treated with nicotine patches returned to baseline levels of inflammatory cytokines TNF-α and IL-6 at a faster rate. The authors propose that nicotine administration could aid in a faster resolution of inflammation in patients with systemic endotoxemia (54). In a similar study, 17 healthy, non-smoking males aged 18 to 35 were included in an LPS administration model of systemic inflammation with a nicotine patch intervention. Unlike the Wittebole study (54), the participants were not blinded to their treatments nor was there a placebo control group, and the authors found no effect of nicotine on cytokine release or pain perception after LPS administration (55).

A Cochrane Review investigated the effect of transdermal or intranasal nicotine administration on post-operative pain, opioid analgesic use and opioid-related adverse events (12). The meta-analysis identified nine randomized, placebo-controlled studies including a total of 666 patients. Nicotine was estimated to reduce post-operative pain scores at 24 h post-surgery by a small, but statistically significant, amount compared with placebo (mean difference of 0.88 on a 0 to 10 scale; 95% CI of −1.58 to −0.18; eight studies). Statistical heterogeneity was substantial and not adequately explained by stratification of studies according to type of surgical procedure, smoking status of the patient, method of nicotine administration or timing of nicotine administration. Nicotine increased the risk of post-operative nausea to a statistically significant extent (relative risk of 1.24; 95% CI of 1.03 to 1.50; seven studies). However, it did not increase the risk of vomiting (risk difference of 0.03; 95% CI of 0.04 to 0.09; seven studies). The authors of the meta-analysis concluded that “nicotine may reduce post-operative pain at twenty-four hours [post-surgery] compared to placebo but the effects were relatively small (less than one point on a ten-point pain scale)” and “nicotine does not appear to reduce post-operative use of opioids or opioid-related adverse events but probably increases the risk of nausea” (12).

The three studies reviewed in this section are listed in Supplementary File 3.

Pulmonary sarcoidosis is a systemic granulomatous disease of unknown cause which affects young to middle-aged adults. It is characterized by the development of non-necrotizing granulomatous inflammation in the absence of identifiable infectious, autoimmune or environmental causes (56). The disease typically involves the lungs, frequently leading to impaired exercise tolerance and associated shortness of breath. The majority of patients with active pulmonary sarcoidosis complain of overwhelming fatigue which often persists despite immune-modulating drugs typically used to treat sarcoidosis (56).

A pilot study noted that treatment of symptomatic pulmonary sarcoidosis patients (n = 7) with transdermal nicotine patches over a twelve-week period, in addition to their existing medications, resulted in an immunological phenotype which was highly comparable to that of asymptomatic patients (57). The daily nicotine dose was increased from 7 mg to 14 mg to 21 mg at one-week intervals from the start of the study. The authors concluded that their results “supported the notion that nicotine treatment may be beneficial in this patient population”.

Carlens et al. carried out a large study investigating chronic inflammatory disease in a cohort of Swedish construction workers, the results of which have been included in several sections of this review. Within that study, there was no effect of exclusive use of Swedish snus on the risk of developing sarcoidosis compared to never use of any tobacco product (14).

A study protocol for a randomized, double-blind, placebo-controlled clinical trial investigating the effect of transdermal nicotine patch administration as a treatment approach for pulmonary sarcoidosis has been published (56). The primary objective outcome of the study was reported as being an improvement in forced vital capacity at study week 26 from baseline measurements. Results from this clinical trial have recently been published and indicated that treatment with transdermal nicotine patches (21 mg daily) over a 26-week period was associated with a clinically significant, approximate 2.1% (70 mL) improvement in forced vital capacity (FVC) from baseline to 26 weeks (58). FVC decreased by a similar amount (2.2%) in the placebo group with a net increase of 140 mL (95% confidence intervals of 10 mL to 260 mL) when comparing nicotine and placebo treatment groups at 26 weeks. No improvements were observed in lung texture scores, fatigue assessment scores, St George’s Respiratory Questionnaire Score or the Sarcoidosis Assessment Tool. The study was, however, underpowered to show the expected treatment effect for nicotine treatment, and despite randomization there were large baseline differences in FVC.

The three studies reviewed in this section are listed in Supplementary File 3.

In their 2009 study, Hedström et al. showed that there was an increased risk of developing multiple sclerosis (MS) in smokers, which did not reflect the risk seen in snus users, even when adjusted for smoking. In fact, the results suggested snus use may have an inverse association with development of the disease compared to never users of snus (59). Data from their follow-up study from two Swedish population-based case-control studies was used to estimate the association between snus use and risk of developing MS. The combined studies had a total of 7,883 cases and 9,437 controls respectively and were matched for age, gender and residential area. Of these participants, 223 cases and 392 controls used snus but had never smoked. Results indicated that these exclusive snus users had a statistically significant decreased risk of developing MS compared to those who had never used snus (odds ratio of 0.75; 95% CI of 0.63 to 0.90). An inverse dose-response correlation between cumulative dose of snus use and the risk of developing MS was also observed. The authors concluded that they had “found clear evidence of an inverse dose-response correlation between cumulative dose of snuff [snus] use and the risk of developing multiple sclerosis. Nicotine, by targeting alpha 7 nicotinic receptors, exerts anti-inflammatory and immune-modulation effects in a way that might decrease the risk of developing multiple sclerosis” (60).

In contrast to this finding, a study investigating chronic inflammatory disease in Swedish construction workers, reported that exclusive use of Swedish snus was associated with a marginally increased risk of MS compared to never tobacco users (relative risk of 1.8; 95 % CI of 1.1 to 2.9) (14). The authors could not offer an explanation for their findings, although they did point out that they had limited information about other risk factors for disease in their participants and the result was of “borderline statistical significance”, and therefore, may be due to unknown confounding.

UC dominated the literature related to digestive diseases, contributing 14 studies out of the 19 studies analyzed in this section. Each of the studies varied greatly in terms of participant number, study design and study endpoints. Two meta-analyses were carried out. McGrath et al. focused on whether nicotine had an effect on achieving remission in UC patients (24) whereas Nikfar et al. aimed to assess the efficacy and tolerability of nicotine whilst also achieving remission in UC patients (35). Both studies included five clinical trials in their analysis and had four in common. Despite these similarities, the authors drew different conclusions, with McGrath et al. finding that nicotine was significantly better than placebo for achieving remission although there was little clinical advantage for its use, whereas Nikfar et al. concluded that their data did not support a role for nicotine in achieving remission in UC patients. The high number of adverse events and withdrawals in relation to nicotine application may explain these differences in conclusion.

Studies investigating nicotine in relation to clinical improvements in patients with UC seem to more consistently suggest a beneficial role of nicotine, especially when used in conjunction with traditional therapies such as mesalazine and corticosteroids (17, 18, 34). As Lashner et al. pointed out in their study, it seems that nicotine can elicit an anti-inflammatory response in some UC patients, however, its use is probably most appropriately assessed on a case-by-case basis (29). Mode of delivery and dose are also key to the effects and adverse effects observed, although a change in interleukin 2 and 8 expression in response to nicotine does support an anti-inflammatory role within the context of UC as a disease (19, 20).

In contrast to the relatively large body of evidence surrounding the use of nicotine as a treatment in patients with UC, very few studies have been published in relation to other digestive diseases. Ingram et al. (13) reported clinical improvement in ten patients with Crohn’s disease who were treated with nicotine enemas and Carlens et al. (14) reported no increased risk of developing Crohn’s disease in exclusive users of Swedish snus. These two studies are insufficient to support an inflammatory role of nicotine, pro- or anti-.

Two studies investigated the use of nicotine as a treatment for primary sclerosing cholangitis, one using transdermal treatment (36) and the other oral treatment (37). Vleggaar et al. (36) showed no significant effect of nicotine in their participants. Angulo et al. (37) saw almost all of their participants drop-out of their already small study, suffering adverse effects. Although both negative, only 20 participants were included across both studies combined, therefore leaving the question of whether nicotine could be an effective treatment for PSC unanswered.

Finally, in this section a single study assessed whether nicotine could reduce the inflammatory response in the gut post-surgery. Nicotine gum was used as the mode of delivery; however, no overall benefit was seen in the 40 participants who took part.

Six papers were analyzed in relation to the potential effects of nicotine on atherosclerosis via inflammatory pathways. All the studies recruited current smokers and therefore the results are heavily confounded. Three of the studies investigated acute cardiovascular responses after use of electronic cigarettes as their mode of nicotine delivery, measuring markers of endothelial function such as endothelial progenitor cells and extracellular vesicles (41, 44, 45). Unfortunately, the full characteristics of the measured biomarkers are not known, so it is impossible to conclude whether the effects observed are pro- or anti-inflammatory in nature.

Two studies found no effect of nicotine replacement therapies on inflammatory markers associated with atherosclerotic formation (40, 42). One study found a beneficial effect of nicotine replacement therapies on markers of vascular inflammation compared to continued smoking. This is not necessarily surprising, given the relationship between smoking and cardiovascular disease (61); however, as there was no comparator group of never smokers, it is impossible to state that the decrease in inflammatory markers observed was as a result of nicotine administration or as a result of the removal of other pro-inflammatory agents found in cigarette smoke (43).

Overall, the data surrounding the relationship between nicotine and atherosclerosis is inconclusive. Mechanisms have been proposed via in vitro and in vivo animal studies involving particularly the activation of α7 nicotinic receptors. However, there is also conflicting evidence arising from these models (39). Longitudinal studies in human participants that consider smoking history will be necessary to assess the risk of atherosclerosis in relation to nicotine use and inflammation.

Five studies addressed the effect of nicotine on inflammatory conditions of the skin, although these were spread across a range of conditions. Two very small studies in participants with Behçet’s disease both described positive clinical outcomes when nicotine was administered via transdermal patch or gum (51, 52). In two other studies that used transdermal patch administration, an anti-inflammatory effect of nicotine was shown in response to dermal irritation and to symptoms of eosinophilic pustular folliculitis (48, 49). A systematic review of the effect of nicotine on wound healing, however, showed mixed results. Analysis of six studies suggested that nicotine may have an anti-inflammatory effect on the wound healing process, whilst maintaining other proliferative and angiogenic mechanisms. Overall, no beneficial or detrimental effect was recognized (50).

Although there was an anti-inflammatory effect of nicotine observed in all five of the studies included in this section, the small study sizes and confounding smoking histories of the participants mean that the evidence is insufficient to support an anti-inflammatory effect of nicotine on human skin conditions or healing.

Three small studies (maximum participant number = 20) were reviewed in relation to pain and infection. One study related to post-operative pain management and reported positive outcomes of nicotine administration on both pain and oedema. Two studies used a LPS administration as a model of systemic inflammation; the first showed no effect of nicotine patch application on relieving any of the associated symptoms; the other showed a faster resolution of inflammation in the participants who received nicotine patch treatment. A fourth study reviewed in this section was a Cochrane systematic review and meta-analysis, which analyzed nine studies with a total of 666 participants and concluded that there was a small but positive effect of nicotine on post-operative pain. Although these results support an anti-inflammatory role for nicotine in the resolution of pain and infection, it should be noted that adverse effects of nicotine were repeatedly cited. Nicotine administration in never smokers can lead to symptoms of mild nicotine adverse effects, such as nausea, vomiting and increased heart rate, which unless managed with careful dosing, is likely to nullify the positive effects of nicotine over the use of other established analgesics.

Three studies regarding pulmonary sarcoidosis were identified. Two addressed treatment of active symptoms with transdermal nicotine patches (57, 58) and the other investigated the risk of developing pulmonary sarcoidosis in users of nicotine-containing products (14). As in the studies that suggested improvement of inflammatory skin conditions with nicotine application, significant clinical improvement was observed in the small group of patients treated with nicotine for their pulmonary sarcoidosis. No effect on the risk of developing pulmonary sarcoidosis was seen in the 37,459 cohort participants who exclusively used snus. The results of these three separate studies cannot be compared as the risk of developing disease is a distinct process from treatment of symptoms when disease has already manifested.

Three studies were analyzed in relation to nicotine use and risk of developing MS, all of which were carried out in Swedish cohorts and all investigated snus as the mode of nicotine delivery (14, 59, 60). Despite the similarities in the studies, conflicting results were found. Hedström et al. (59) reported an inverse relationship between snus use and onset of MS, compared to Carlens et al. (14) who showed a marginally increased risk of developing MS in exclusive snus users compared to never users of any tobacco product. The authors point out that their findings may be as a result of residual confounding. It should also be noted that although snus offers a method of nicotine delivery that is devoid of smoke, other tobacco constituents are also present within the product, meaning that the role of nicotine in complete isolation cannot be elucidated. In addition, correlations between product use and inflammatory disease risk investigated in these studies were not supported by any investigation into the levels of inflammatory markers in any of the participants, leaving a large piece of the puzzle missing.

The role of nicotine in the development of MS remains unclear. No studies exist in humans where nicotine is administered as a potential treatment of MS symptoms, and therefore its role in the inflammatory pathways of this disease remains unknown.