Nickel (Ni) is one of the most widespread transition metals in the environment and a leading cause of allergic contact dermatitis (ACD) worldwide.^[1] Beyond its dermatologic implications, nickel exposure may elicit systemic immune reactions that extend to the respiratory tract, particularly in sensitized individuals. Nickel compounds are used extensively in alloys, jewelry, cosmetics, and industrial products; therefore, both cutaneous and inhalational exposures are common.^[2] Although the skin is the primary site of sensitization, increasing evidence indicates that nickel may also affect mucosal immunity and pulmonary physiology through inflammatory and oxidative mecha- nisms.^[3] Nickel allergy affects approximately 10%–20% of adults, with a marked predominance in women, attributed to frequent contact with nickel-containing jewelry and personal items.^[4] The immunopathogenesis of nickel hypersensitivity involves a type IV delayed hypersensitivity response mediated by CD4⁺ and CD8⁺ T lymphocytes. Upon re-exposure, nickel ions penetrate the epithelial barrier and bind to endogenous proteins, forming hapten-protein complexes that activate antigen-presenting cells.^[5] Subsequent cytokine release, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-17 (IL-17) sustains a proinflammatory environment.^[6]

Although well characterized in the skin, these mechanisms may also be activated within the respiratory mucosa following inhalational exposure to nickel containing particles (Fig. 1).

Epidemiological studies show that 12%–18% of nickel‑sensitized individuals exhibit respiratory symptoms such as episodic wheeze or cough, increasing the clinical relevance of pulmonary evaluation.^[7]

In the respiratory system, nickel compounds interact directly with epithelial cells lining the bronchi and alve- oli.^[8] Experimental data demonstrate that nickel nanoparticles can induce epithelial injury, tight-junction disruption, and the release of proinflammatory cytokines including IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF).^[9] These mediators promote recruitment of neutrophils and eosinophils, contributing to airway inflammation and mucus hypersecretion.^[10] In sensitized individuals, nickel may amplify Th2-mediated immune responses, leading to enhanced expression of IL-4, IL-5, and IL-13, cytokines known to promote airway hyperreactivity and remodeling.^[11]

This inflammatory milieu mirrors aspects of allergic asthma, suggesting that nickel hypersensitivity may precipitate reversible functional impairment even in the absence of chronic respiratory disease.^[12] Nickel-induced oxidative stress represents another critical pathway linking exposure to pulmonary dysfunction. Reactive oxygen species (ROS) generated by nickel can activate redox-sensitive transcription factors such as nuclear factor κB (NF-κB) and activator protein-1 (AP-1), leading to the upregulation of inflammatory genes.^[13] Mitochondrial dysfunction and lipid peroxidation further perpetuate epithelial injury. These oxidative mechanisms also modulate the expression of heme oxygenase-1 and superoxide dismutase, indicating a cellular effort to counteract oxidative injury.^[14] Over time, chronic oxidative imbalance may impair mucociliary clearance and increase airway resistance, contributing to reductions in forced expiratory volume (FEV₁) and peak expiratory flow (PEF). Such effects are consistent with spirometry alterations observed in occupational settings involving nickel exposure.^[15] The downstream consequence of persistent airway inflammation and oxidative stress is hyperreactivity of bronchial smooth muscle.^[16] Nickel exposure increases intracellular calcium levels and sensitizes β-adrenergic pathways, leading to bronchoconstriction.^[17] In animal models, nickel chloride inhalation provokes airway hyperresponsiveness accompanied by elevated eosinophilic infiltration and peribronchial inflammation.^[18] Importantly, these changes are not necessarily irreversible. Studies show that nickel withdrawal or avoidance can reduce cytokine production, restore epithelial integrity, and normalize airway mechanics within weeks.^[19]

This reversibility underscores the importance of early recognition and management of nickel induced respiratory manifestations.^[20] Females represent the majority of nickel-sensitized individuals and often present with a combination of dermatological and mild respiratory symptoms such as cough, dyspnea, or throat irritation after expo- sure.^[21] The interplay between cutaneous and airway sensitization suggests a shared immunologic pathway.^[22] Moreover, hormonal influences on immune modulation may further enhance susceptibility to nickel-induced airway effects in women.^[23] Given the global rise in environmental allergens, understanding how nickel sensitization impacts pulmonary function in this population has both clinical and preventive significance.^[24]

Despite increasing recognition of systemic manifestations of metal hypersensitivity, few studies have examined pulmonary function in non-occupationally exposed individuals with confirmed nickel allergy.^[25] The potential reversibility of nickel-associated airway impairment following allergen avoidance remains insufficiently explored.^[25] In this context, the present study evaluated the pulmonary functional parameters in female patients with confirmed nickel sensitization before and after a structured nickel avoidance period.

By focusing on reversible changes in spirometry indices such as FVC, FEV₁, PEF, and FEV₁/FVC ratio, this study provides novel insight into the functional respiratory consequences of nickel allergy and the potential benefits of avoidance strategies.

This study provides novel evidence that nickel hypersensitivity in women may be associated with reversible pulmonary function impairment, with significant improvements in spirometric parameters following a structured three-month nickel-avoidance program. Although nickel allergy is well established as a major cause of contact dermatitis, its potential systemic and respiratory implications remain largely underexplored, particularly in non-occupationally exposed individuals.^[28] The current findings therefore broaden the clinical understanding of nickel sensitization beyond dermatological manifestations, suggesting that the allergen may also exert functional effects on the respiratory system that are at least partially reversible upon avoidan- ce.^[29]

The present cohort consisted exclusively of female patients, consistent with the known epidemiology of nickel hypersensitivity, which disproportionately affects women due to higher exposure to nickel-releasing jewelry and personal items. Nickel is a potent immunologic hapten capable of inducing type IV delayed hypersensitivity reactions, involving activation of T-lymphocytes, macrophages, and pro-inflammatory cytokine release (IL-1β, TNF-α, IFN-γ).^[30] Repeated dermal exposure or systemic absorption of nickel may prime both skin and airway epithelial immune responses, promoting localized inflammation and oxidative stress that could transiently alter pulmonary function.^[31]

The observed improvements in FVC, FEV₁, PEF, and FEV₁/FVC ratio following nickel avoidance were not only statistically significant but also clinically meaningful, with large effect sizes (d_z=1.27–1.97). These magnitudes exceed those reported in studies of mild asthma or allergic rhinitis after short-term allergen reduction^[32], suggesting that nickel sensitization may contribute to measurable yet reversible airway dysfunction. Mechanistically, the inhalation or ingestion of trace nickel may act as a non-specific airway irritant, triggering epithelial activation, neutrophil recruitment, and oxidative injury.^[33] Experimental data show that nickel nanoparticles can increase airway resistance and induce bronchial inflammation in animal models^[34], while occupational studies have demonstrated diminished FEV₁ among nickel refinery workers^[35]. The current study extends this evidence to a non-industrial, female population with contact hypersensitivity rather than direct occupational exposure.

Subgroup analyses in this cohort revealed that women with normal BMI (<25 kg/m²) experienced significantly greater functional recovery compared to overweight subjects. This aligns with previous observations that obesity is associated with reduced lung compliance, increased airway closure, and systemic low-grade inflammation, all of which may blunt responsiveness to environmental or therapeutic interventions.^[36] Conversely, the absence of significant differences between smokers and non-smokers suggests that, within the small number of current smokers in this sample, tobacco exposure did not markedly influence the direction of nickel-related functional changes, although the sample size limits firm conclusions.

An additional finding of note is the improvement in mid-expiratory flow rates (FEF_25-75%), which are sensitive markers of small-airway function. This supports the hypothesis that nickel-induced inflammation may primarily affect distal airways. The normalization of these indices after nickel avoidance is consistent with a reduction in small-airway obstruction, as previously observed in allergic asthma after exposure cessation.^[21] Collectively, these data reinforce the pathophysiological link between allergic sensitization and subclinical bronchial hyperreactivity.

While the exact mechanism through which nickel avoidance improves lung function remains yet unclear, several plausible pathways exist. Removal of cutaneous and dietary sources of nickel likely decreases systemic nickel absorption and circulating nickel ions, reducing systemic oxidative stress and cytokine release, while minimizing respiratory exposure—for example, from household dust or metal vapor—may attenuate airway irritation. Further, nickel avoidance may indirectly improve pulmonary performance through enhanced mucociliary clearance and reduced epithelial inflammation. Together, these processes could explain the observed reversibility in spirometric measures.

From a clinical standpoint, these results underscore the importance of multidisciplinary assessment of nickel-sensitized patients who report respiratory complaints. Dermatologists and allergologists should consider incorporating spirometric screening into routine evaluation, particularly for female patients with co-existing respiratory symptoms. Education on allergen avoidance, often emphasized for cutaneous disease management, may also have systemic benefits. Early identification and avoidance could prevent progression to chronic airway disease in susceptible individuals.

Despite its strengths, this study has several limitations. The sample size (n=12) was relatively small, reflecting the strict inclusion criteria and the observational design. Nevertheless, the within-subject analysis and large effect sizes mitigate some of the concerns regarding power. The absence of a non-sensitized control group limits causal inference, and confounding factors such as environmental pollution or unrecognized atopy could not be fully excluded. Spirometric testing, while dependable, provides only functional data; future studies incorporating biomarkers of oxidative stress and airway inflammation (e.g., fractional exhaled nitric oxide, eosinophilic cationic protein) would strengthen mechanistic interpretation. Longitudinal studies with larger samples and both sexes are warranted to assess persistence and generalizability of the observed improvements.

Finally, although the nickel avoidance protocol was standardized and monitored, adherence relied partially on self-reporting, which may introduce bias. Objective measures such as nickel levels in urine or serum could enhance future methodological rigor. Nonetheless, the consistent direction and magnitude of functional improvement across all participants suggest genuine physiological recovery rather than measurement variability.

This study demonstrates that nickel sensitization in women may be associated with reversible impairment of pulmonary function, independent of occupational exposure. A structured three-month program of nickel avoidance led to significant and clinically relevant improvements in FVC, FEV₁, PEF, and FEV₁/FVC ratio. These findings highlight the systemic implications of metal allergies and support the integration of pulmonary function testing into the clinical management of nickel-sensitized patients, particularly those with concomitant respiratory complaints.

The results advocate for a more holistic approach to nickel allergy that extends beyond dermatologic care to include respiratory evaluation and lifestyle counseling. Incorporating allergen-avoidance strategies may improve both skin and airway outcomes, enhancing overall quality of life.

Future research should explore immunologic and inflammatory biomarkers, involve larger cohorts with control groups, and evaluate long-term outcomes following sustained avoidance. A broader understanding of the respiratory impact of metal sensitization may inform both preventive strategies and multidisciplinary management in allergy and dermatology practice.

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Faculty of Medicine and the Institute of Pathophysiology (Approval No. 111062;UCCK-2022-41/FM=KMC-2025/5).

The authors declared that no clinical trials were used in the present study.

The authors declared that certain experiments on humans or human tissues were performed for the present study.

The authors declared that written informed consent was obtained from all participants before enrollment in the study.

The authors declared that no experiments on animals were performed for the present study.

The authors declared that no commercially available immortalized human and animal cell lines were used in the present study.

No external funding was received.

The author declares no conflict of interest.

All data used are referenced or included in the article.

The authors used ChatGPT to modify and polish the Cover Letter in order to comply with the Folia Medica journal’s requirements during the preparation of this work.

BN and SD: conceptualization, study design, drafting the manuscript, critical review of the manuscript; SD and ShD: statistical analysis, interpretation of data, data collection; BN: literature review, data verification, manuscript editing. All authors have read and agreed to the published version of the manuscript.