ABSTRACT
Background
Benign tracheal stenosis, characterized by granulation hyperplasia, is a rare and serious disease threatening human health. Interventional bronchoscopy demonstrates limited therapeutic efficacy and poses a risk of re‐injury to the airway. The objective of this meta‐analysis is to evaluate the efficacy of pharmacological therapy in preclinical models of tracheal stenosis.
Method
We conducted an extensive literature search across PubMed, EMBASE, Web of Science, and Cochrane Library from inception to January 31, 2024. Studies evaluated the efficacy of various pharmacological agents in treating tracheal stenosis. The SYRCLE bias risk tool was utilized to evaluate potential bias, and the GRADE approach was used to assess the quality of evidence for each outcome. Primary outcomes included the stenosis index (SI) and the degree of tracheal stenosis (SD). Secondary outcomes comprised additional indicators relevant to evaluation of tracheal stenosis, such as the fibrosis indexes, the ratio of the lamina propria thickness to the cartilage (LCR), and the severity of inflammation. Meta‐analysis was conducted via Cochrane Collaboration Review Manager (version 5.4).
Results
A total of 7554 studies related to pharmacological therapies for benign airway stenosis were reviewed, of which 34 articles met inclusion criteria for this meta‐analysis following study selection. Of these, five studies evaluated SI, 17 studies evaluated SD, and six studies evaluated the fibrosis indexes. Compared to the control group, pharmacological therapy was associated with a significant reduction in SI (weighted mean difference (WMD) −0.21, 95% CI: −0.33 to −0.10, p < 0.001, I 2 = 82%), SD (WMD = −0.26; 95% CI: −0.34 to −0.18; p < 0.001, I 2 = 93%), and the fibrosis indexes (WMD = −3.15; 95% CI: −4.4 to −1.9; p < 0.001, I 2 = 82%).
Conclusion
Various pharmacological agents exhibited different efficacies in alleviating tracheal stenosis symptoms. These findings provide valuable insights into prospective therapeutic strategies.
Keywords: benign tracheal stenosis, efficacy, granulation tissue, pharmacological therapy, preclinical studies
1. Introduction
Benign tracheal stenosis is a significant medical condition resulting from various nonmalignant factors, including tracheobronchial tuberculosis, prolonged tracheal intubation or tracheotomy, foreign bodies, benign bronchial tumors, tracheal bronchomalacia, recurrent polychondritis, Wegener's granulomatosis, aspiration injuries, and amyloidosis [1]. Notably, the incidence of benign central tracheal stenosis associated with prolonged intubation can reach as high as 21% [2]. Clinical manifestations in patients with tracheal stenosis range from dyspnea to life‐threatening experiences. The underlying mechanisms of benign central tracheal stenosis remain poorly understood, which may involve abnormal repair processes, inflammatory cell infiltration, and fibrosis following airway injury. This pathological response leads to the formation of highly proliferative granulation tissue and excessive extracellular matrix (ECM) deposition that constricts the subglottic and/or proximal tracheal airway [3, 4].
The pathogenesis of tracheal stenosis and its variations across different etiologies are not well elucidated, which is a barrier to improving medical treatment of tracheal stenosis. Specifically, treatment strategies for managing tracheal stenosis continue to be contentious without an international consensus on optimal therapeutic approaches [5]. Recently developed interventional bronchoscopy techniques have shown promise in alleviating symptoms associated with benign tracheal stenosis through methods such as balloon dilation, laser surgery, argon plasma coagulation (APC), cryotherapy, stent placement, and combined interventional therapies [6, 7, 8]. However, interventional bronchoscopy has a limited therapeutic efficacy and poses a risk of re‐injury to the airway leading to hyperplasia of granulation tissue and scar formation [9]. Consequently, regular assessment of the stenosis severity along with prevention strategies against restenosis and recurrent granulation hyperplasia, minimally invasive interventions, and cost‐effective pharmacological treatments are crucial for effective management.
With ongoing research developments, several pharmacological agents have been identified as beneficial in reducing restenosis risk while alleviating respiratory difficulties. For instance, transcutaneous point‐of‐care ultrasound (POCUS) guided submucosal paclitaxel injection has been reported to alleviate tracheal stenosis by reversing collagen deposition within the anterior wall of the trachea [10]. Mizokami et al. demonstrated that low‐dose systemic tacrolimus exerts a preventive effect on laryngotracheal stenosis by inhibiting immune cells' activation within the injured airway mucosa via the calcineurin/nuclear factor activated T cell/interleukin 2 pathway [11]. Additionally, mitomycin C is frequently utilized adjunctively to prolong the time until symptomatic recurrence occurs in laryngotracheal stenosis. While the application of mitomycin C is considered safe, its efficacy in reducing the recurrence of stenosis remains a subject of ongoing debate [12]. Furthermore, certain traditional Chinese medicines, including β‐elemene [13], quercetin [14], and plumbagin [15], have demonstrated effectiveness in mitigating tracheal stenosis through various biological mechanisms. Despite numerous animal studies investigating tracheal stenosis, the safety, feasibility, and efficacy of different pharmacological agents require further evaluation.
In this context, the objective of this meta‐analysis was to summarize the effects of various drugs on treating tracheal stenosis in animal models. To the best of our knowledge, no prior studies have aggregated pharmacological therapies across different animal models for preventing benign tracheal stenosis. Consequently, we conducted a meta‐analysis of the literature to evaluate the efficacy of diverse pharmacological therapies in animals with tracheal stenosis.
2. Methods
2.1. Data Source and Search Strategies
This meta‐analysis followed the Meta‐analysis checklist (Table S1). A comprehensive literature search was executed for animal studies focusing on pharmacological therapy related to benign tracheal stenosis using databases such as PubMed, EMBASE, Web of Science, and Cochrane Library from inception to January 31, 2024. The detailed search strategy is outlined in Table S2. The language restriction was set to English only.
2.2. Eligible Criteria
Studies were included in this meta‐analysis based on the following inclusion criteria: (1) involvement of animal models exhibiting benign tracheal stenosis (across all species and sexes); (2) administration of pharmacological therapy to all benign tracheal stenosis animal models; (3) inclusion of evaluations pertaining to tracheal stenosis; (4) incorporation of efficacy outcomes such as the stenosis index (SI) and degree of tracheal stenosis; and (5) presence of a control group.
Studies were excluded from the meta‐analysis for the following reasons: (1) failure to meet all inclusion criteria; (2) classification as case reports, case series, meeting abstracts, review, or meta‐analysis; and (4) studies published in a non‐English language.
2.3. Study Selection and Data Extraction
Two investigators independently screened the literature in accordance with the established search strategy. Any disagreements were reviewed and resolved by a third investigator. Following the identification of articles that met both inclusion criteria and exclusion criteria, we extracted the data using a standardized collection form that included details such as the first author, year of publication, animal characteristics (species, gender, and model), intervention specifics (medication type, administration route, dosage, time of therapy posttracheal stenosis induction, and follow‐up duration), evaluation indicators, evaluation methods, and outcomes.
2.4. Assessment of Risk of Bias (RoB) and GRADE
The risk of bias was evaluated utilizing the Meta‐analysis Centre for Laboratory animal Experimentation (SYRCLE) bias risk tool [16]. This RoB tool comprises 10 entries related to six types of bias: selection bias (sequence generation, baseline characteristics, and allocation concealment), performance bias (random housing and blinding), detection bias (random outcome assessment and blinded outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective outcome reporting), and other biases. Each entry categorized studies as having high, low, or unclear risk of bias.
The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. GRADE was used to rate the certainty of evidence for each outcome (high/moderate/low/very low), with downgrading for bias, inconsistency, indirectness, imprecision, or publication bias.
2.5. Primary and Secondary Outcomes
The primary outcomes assessed in this meta‐analysis were the SI and the degree of tracheal stenosis (SD). Secondary outcomes included additional indicators pertinent to evaluation of tracheal stenosis, such as the lamina propria (LP) thickness, width of stoma, the ratio of the LP thickness to the cartilage (LCR), collagen formation, the fibrosis indexes, and the severity of inflammation.
2.6. Directed Acyclic Graphs (DAGs)
DAGs were used to identify potential confounding variables and guide the adjustment strategy. Based on prior knowledge and causal assumptions, we elucidated the pathway from pharmacological intervention to fibroblast inhibition and subsequently to stenosis reduction.
2.7. Statistical Analysis
Statistical analysis was conducted using Cochrane Collaboration Review Manager (version 5.4). Continuous outcomes were expressed as weighted mean differences (WMDs) with 95% confidence intervals (CIs). Heterogeneity was assessed using the chi‐squared test and I 2 statistic. A fixed‐effect model was applied when p > 0.1 and I 2 < 50%; otherwise, a random‐effect model was used. In cases of significant heterogeneity, subgroup analyses were performed for further exploration. Publication bias was evaluated using funnel plots. A two‐sided p < 0.05 was considered statistically significant.
3. Results
3.1. Study Selection
Following our search strategy, we identified 7554 studies related to pharmacological therapies for benign airway stenosis, and 1765 duplicate articles were eliminated using Endnote X9 software. A total of 5689 articles were excluded based on title and abstract reviews. One hundred articles underwent full‐text review. Ultimately, 34 articles were incorporated into this meta‐analysis after study selection (Figure 1). (If a single study provided more than one intervention, each intervention was treated independently.)
FIGURE 1.
Flow diagram of the study selection.
3.2. Study Characteristics
The basic characteristics of the 34 articles included in this meta‐analysis are presented in Table 1. These publications span from 1992 to 2023 and feature sample sizes ranging from 10 to 60 subjects. A significant number of studies utilized New Zealand white rabbits as their model organisms. One study was conducted with ferrets. The leading three countries contributing to article publication are China, the USA, and Turkey. In most studies involving benign tracheal stenosis animal models, mechanical injury was employed for induction purposes. Twenty distinct drugs have been investigated for treating benign airway stenosis at varying dosages, including paclitaxel, phlorotannins, tacrolimus, nintedanib, β‐elemene, Don, halofuginone, tanshinone IIA, plumbagin, mitomycin‐C, erythromycin, 5‐fluorouracil (5‐FU), and so on. Most were administered topically or intraperitoneally shortly after induction in animal models of benign tracheal stenosis. Additional seven articles encompassed multiple drug investigations. The most common route of administration in these studies was topical application. The follow‐up durations postpharmacological therapy were lasting a minimum of 1 day. Thus, the articles included a total of 34 animal studies involving 873 animals [10, 11, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45].
TABLE 1.
General characteristics of preclinical studies investigating the efficacy of pharmacological therapy in a model of benign airway stenosis.
| Author (year) | Country | Species, strain, gender | No. of the sham group | No. of controls | No. of treated animal | Tracheal stenosis model | Medicine | Medicine dose | Medicine route | Control medicine | Time of medicine therapy after stenosis (days) | Follow‐up (days) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Deng et al. (2023) [10] | China | Japanese white rabbit, M | 5 | 5 | 5 | Mechanical injury | Paclitaxel | 0.6 mg | Submucosal injection | Saline | 10 days (only once time) | 7 days |
| Lee et al. (2022) [17] | Korea | SD rats, M | / | 7 | 7 | Surgical injury | PT and BL | PT 100 μg/mL and BL 12 J/cm2 | Combined treatment | / | 0–3 days | 10 days |
| Mizokami et al. (2015) [11] | Japan | SD rats, M | / | 6 | 13 | Mechanical injury | Tacrolimus |
High‐dose tacrolimus: 1 mg/Kg Low‐dose tacrolimus: 0.2 mg/kg |
Intramuscular injection | / | Beginning 1 day before the scraping (for 5 days) | 9 days |
| Huang et al. (2023) [18] | China | New Zealand White rabbits, M/F | / | 10 | 10 | Electrocautery | CM‐chitosan | 5 mg/mL 3 mL for 15 min | Nebulizer inhalation | Saline | Once per day on postoperative days | 14 days, 28 days |
| Wei et al. (2020) [19] | China | New Zealand White rabbits, M/F | 6 | 6 | 12 | Mechanical injury | Nintedanib/BUD | 10 mg/kg/0.05 mg/kg | Aerosol inhalation | Saline | Twice a day on postoperative days | 10 days |
| Zhang et al. (2021) [13] | China | New Zealand White rabbits, M | / | 8 | 8 | Mechanical injury | β‐elemene | 0.1 mL of 160 μg/mL | Injected into the tracheal granulation | 0.1 mL of 1% DMSO | 1 week after modeling | 14 days, 28 days |
| Xiao et al. (2021) [14] | China | White rabbits, M/F | 6 | 6 | 6 | Mechanical injury | Quercetin | 120 mg/kg/day | Nasogastric administration | Saline | 0–10 days | 11 days |
| Tsai et al. (2021) [20] | USA | C57BL/6 mice, NR | / | 15 | 15 | Chemo‐mechanical injury | Don | 1.3 mg/kg | Intraperitoneal injection | PBS | After 4 days after surgery | 7 days, 14 days |
| Ertuğrul et al. (2007) [21] | Japan | SD rats, M/F | / | 8 | 8 | Mechanical injury | Halofuginone | 0.1 mg/kg/day | Intraperitoneal injection | / | 0–30 days | 30 days |
| Ertuğrul et al. (2009) [22] | Japan | SD rats, M/F | / | 8 | 8 | Mechanical injury | Halofuginone | 30 mg/dL | Topical applications | / | On operative day | 30 days |
| Duan et al. (2016) [23] | China | SD rats, NR | / | 20 | 25 | Surgical injury | Tanshinone IIA | 25 mg/kg/day | Intraperitoneal injection | Saline | 0–90 days | 90 days |
| Olmos‐Zuñiga et al. (2017) [24] | Mexico | Wistar rats, M/F | / | 10 | 10 | Surgical injury | Pirfenidone and collagen‐PVP | 40 mg/kg/day Pirfenidone and 2.5 mg collagen‐PVP | Oral administration and topical application | Saline | 0–28 days | 28 days |
| Shi et al. (2021) [15] | China | SD rats, M | 6 | 6 | 6 | Mechanical injury | Plumbagin | 4 mg/kg/d | Intraperitoneal injection | Saline | 0–9 days | 9 days |
| Huang et al. (2020) [25] | China | Rabbits, NR | / | 6 | 12 | Mechanical injury | ERY/ERY + BUD | ERY (13.6 mg/kg)/BUD (0.05 mg/kg) | Gavage administration/atomization inhalation | Saline | 7 days before and 10 days after the surgery (twice a day) | 11 days |
| Qin et al. (2018) [26] | China | New Zealand White rabbits, M | 6 | 6 | 42 | Surgical injury | AMK/BUD/ERY/PEN/AMK + BUD/ERY + BUD/PEN + BUD | AMK (200 mg/day), BUD (1000 μg/day), ERY (300 mg/day), PEN (8 × 105 U/day) |
AMK: gavage administration BUD: atomization inhalation ERY and PEN: intramuscular injection. |
Saline | From 7 days before until 10 days after the surgery (twice a day) | 11 days |
| Mao et al. (2011) [27] | China | New Zealand White rabbits, M/F | 12 | 12 | 12 | Mechanical injury | 5‐FU ethosomes | 0.4 mg/mL | Topical applications | 5‐FU | 0, 7, 14, and 21 days | 21 days |
| Guven et al. (2011) [28] | Turkey | Wistar‐Albino rats, NR | 7 | 7 | 14 | Surgical injury |
Group 1: 5‐FU/TA Group 2: carnitine Group 3: DEX |
5‐FU/TA: 5 mg carnitine: 100 mg/kg/day DEX: 0.1 mg/day |
5‐FU/TA: intratracheal injection; carnitine: Intraperitoneal injection DEX: Intramuscular injection |
/ | 0–20 days | 30 days |
| Ingrams et al. (2000) [29] | England | New Zealand White rabbits, NR | / | 19 | 20 | Surgical injury | 5‐FU and TA | 10 mg | A new drug delivery system | Hyaluronic acid gel | On operative day | 12 weeks |
| Elizabeth et al. (2016) [30] | USA | C57BL/6 mice, NR | / | 8 | 8 | Chemical injury and transplanted into the deep subcutaneous tissue | IL‐1RA anakinra | 1 mg/kg | Intraperitoneal injection | Saline | On operative day | 21 days |
| Anton‐Pacheco et al. (2016) [31] | Spain | New Zealand White rabbits, NR | 10 | 20 | 20 | Electrocautery | TGF‐β1 antagonist | 2 mg/mL | Topical applications and intravenous injection. | Saline | On operative day | 28 days |
| Simpson et al. (2008) [32] | USA | Mixed‐breed dogs, NR | / | 4 | 4 | Chemical injury | Anti‐TGF‐β | 5 mg/kg | Topical applications | Saline | 0 day, 5 days | 21 days |
| Çalik et al. (2020) [33] | Turkey | New Zealand White rabbits, M | 8 | 8 | 8 | Tracheostomy | Mitomycin‐C | 0.8 mg/mL | Topical applications | Saline | On operative day | 21 days |
| Ekinci et al. (2017) [34] | Turkey | Winstar Albino rats, F | 8 | 8 | 8 | Standard vertical tracheotomy | Mitomycin‐C and simvastatin | 0.4 mg/day once daily and 30 mg/kg/day | Injected to the paratracheal region and gavage | Saline | On operative day | 21 days |
| Eliashar et al. (1999) [35] | USA | Mongrels, NR | 15 | 15 | 30 | Electrocautery | Mitomycin‐C and repeated Mitomycin‐C | 0.2 mg/ml | Topical application | Saline | 0, 0, and 2 days | 21 days |
| Eliashar et al. (2004) [36] | Israel | Mongrels, NR | / | 7 | 9 | Electrocautery | Dilation combined mitomycin | 0.5 mg/mL | Topical application | Dilation + saline | On operative day | 90 days |
| Iñiguez‐Cuadra et al. (2008) [37] | Spain | New Zealand white rabbits, NR | / | 6 | 12 | Surgical injury | Low‐dose mitomycin, high‐dose mitomycin | 0.2 mg/mL, 0.5 mg/mL | Topical application | Saline | On operative day | 56 days |
| Kuzucuoğlu et al. (2019) [38] | Turkey | SD rats, M | / | 10 | 40 | Surgical injury | Mitomycin‐C | 0.5 mg | Intraperitoneal route/the incision lines/topical administration/inhaled | Saline | On operative day | 28 days |
| Correa et al. (1999) [39] | USA | Mongrel dogs, NR | / | 5 | 5 | Carbon dioxide laser | Mitomycin‐C | 0.01 (1%) | Topical application | / | On operative day | 42 days |
| Roh et al. (2006) [40] | Korea | New Zealand white breeder rabbits, F | / | 20 | 40 | Thermal tissue damage | Mitomycin‐C | Mitomycin‐C 0.4 mg/mL or 10 mg/mL | Topical application | Saline | On operative day | 28 days |
| Cincik et al. (2005) [41] | Turkey | New Zealand White rabbits, NR | / | 16 | 16 | Mechanical injury | Mitomycin‐C/5‐FU/TA | 0.4 mg/mL, 0.2 mL | Topical application | Saline/hyaluronat | On operative day | 14 days, 42 days |
| Gezer et al. (2010) [42] | Turkey | Wistar albino rats, F | / | 7 | 7 | Surgical injury | Tenoxicam | 0.5 mg/kg/day | Intraperitoneal injection | Saline | 0–14 days | 14 days |
| Ghosh et al. (2013) [43] | USA | C57BL6 mice, NR | / | 9 | 10 | Mechanical or chemical injury and LTC transplants | DEX | 0.5 mg/kg | Intraperitoneal injection | / | / | 21 days |
| Gonzalez et al. (1992) [44] | USA | Ferrets, NR | / | 4 | 6 | Mechanical injury | DEX | 8 mg/kg | Aerosolized in an inhalation chamber | / | 2, 4, and 6 h postinjury | 1 day |
| Wistermayer et al. (2020) [45] | USA | New Zealand White rabbits, NR | / | 8 | 8 | Mechanical injury | DEX | 2 mg/kg | Intramuscular injection | Saline | 15 min prior to subglottic injury creation | 7 days |
Note: Follow‐up (days) suggests the observation time of outcomes after pharmacological therapy.
Abbreviations: 5‐FU, 5‐fluorouracil; AMK, amikacin; BL, blue light; BUD, budesonide; CM‐chitosan, carboxymethyl‐chitosan; DMSO, dimethyl sulfoxide; Don, 6‐Diazo‐5‐oxo‐l‐norleucine; ERY, erythromycin; F, female; LTC, laryngotracheal complex.; M, male; NR, not reported; PBS, phosphate‐buffered saline; PEN, penicillin; PT, phlorotannins; PVP, polyvinylpyrrolidone; SD, Sprague Dawley; TA, triamcinolone acetonide; DEX, dexamethasone.
3.3. Assessment of Risk of Bias and GRADE
SYRCLE's RoB tool was utilized to assess the risk of bias within the included studies. All RoB items were shown in Table 2. None of the studies met all 10 criteria indicative of a low risk of bias; only two out of 34 described random sequence generation [17, 18], while merely one implemented blinding methods [19]. Given that most studies did not adequately detail random sequence processes, it is deemed “unclear” regarding bias risk assessment. Baseline characteristics between the intervention and control groups remained comparable across all investigations. The reporting and attrition bias scored as low risk in most studies. In addition, no further sources indicating potential bias were detected.
TABLE 2.
SYRCLE risk of bias assessment for the included studies.
| Author (year) | Random sequence generation? | Baseline characteristics? | Allocation concealment? | Random animal housing? | Blinding of participants and personnel | Blinding of outcome assessment? | Random outcome assessment? | Incomplete outcome data? | Selective reporting? | Other bias? |
|---|---|---|---|---|---|---|---|---|---|---|
| Deng et al. (2023) [10] | U | L | U | U | U | U | U | L | L | L |
| Lee et al. (2022) [17] | U | L | U | U | U | U | U | L | L | L |
| Mizokami et al. (2015) [11] | U | L | U | U | U | U | U | L | L | L |
| Huang et al. (2023) [18] | U | L | U | U | U | U | U | L | L | L |
| Wei et al. (2020) [19] | U | L | U | U | U | U | U | L | L | L |
| Zhang et al. (2021) [13] | U | L | U | U | U | U | U | L | L | L |
| Xiao et al. (2021) [14] | U | L | U | U | U | U | U | L | L | L |
| Tsai et al. (2021) [20] | U | L | U | U | U | U | U | L | L | L |
| Ertuğrul et al. (2007) [21] | U | L | U | U | U | U | U | L | L | L |
| Ertuğrul et al. (2009) [22] | U | L | U | U | U | U | U | L | L | L |
| Duan et al. (2016) [23] | U | L | U | U | U | U | U | L | L | L |
| Olmos‐Zuñiga et al. (2017) [24] | U | L | U | U | U | U | U | L | L | L |
| Shi et al. (2021) [15] | U | L | U | U | U | U | U | L | L | L |
| Huang et al. (2020) [25] | U | L | U | U | U | U | U | L | L | L |
| Qin et al. (2018) [26] | L | L | U | U | U | U | U | L | L | L |
| Mao et al. (2011) [27] | U | L | U | U | U | U | U | L | L | L |
| Guven et al. (2011) [28] | U | L | U | U | U | U | U | L | H | L |
| Ingrams et al. (2000) [29] | U | L | U | U | U | U | U | L | L | L |
| Elizabeth et al. (2016) [30] | U | L | U | U | U | U | U | L | L | L |
| Anton‐Pacheco et al. (2016) [31] | U | L | U | U | U | U | U | L | L | L |
| Simpson et al. (2008) [32] | U | L | U | U | U | U | U | L | L | L |
| Çalik et al. (2020) [33] | U | L | U | U | U | U | U | L | L | L |
| Ekinci et al. (2017) [34] | U | L | U | U | U | U | U | L | L | L |
| Eliashar et al. (1999) [35] | U | L | U | U | U | U | U | L | L | L |
| Eliashar et al. (2004) [36] | U | L | U | U | U | U | U | L | L | L |
| Iñiguez‐Cuadra et al. (2008) [37] | U | L | L | U | L | L | L | L | L | L |
| Kuzucuoğlu et al. (2019) [38] | U | L | U | U | U | U | U | L | L | L |
| Correa et al. (1999) [39] | U | L | U | U | U | U | U | L | L | L |
| Roh et al. (2006) [40] | U | L | U | U | U | U | U | L | L | L |
| Cincik et al. (2005) [41] | U | L | U | U | U | U | U | L | L | L |
| Gezer et al. (2010) [42] | U | L | U | U | U | U | U | L | L | L |
| Ghosh et al. (2013) [43] | U | L | U | U | U | U | U | L | L | L |
| Gonzalez et al. (1992) [44] | U | L | U | U | U | U | U | L | L | L |
| Wistermayer et al. (2020) [45] | L | L | U | U | U | U | U | L | L | L |
Abbreviations: H, high risk of bias; L, low risk of bias; U, unclear risk of bias.
The GRADE evidence profiles for all outcomes are presented in Figure 2. Overall, the certainty of evidence was very low for both the primary outcomes (SI and SD) and the secondary outcomes (fibrosis indexes). The main reasons for downgrading included risk of bias due to lack of blinding, substantial inconsistency across studies (with I 2 values ranging from 83% to 92%), and imprecision resulting from small sample sizes. No outcome was upgraded for a large effect size or a dose–response gradient.
FIGURE 2.
Assessment of GRADE.
3.4. Efficacy of Pharmacological Therapy on Benign Tracheal Stenosis
In this meta‐analysis, 20 animal studies reported SI and/or SD (Table 3). Pharmacological agents showing improvements in SI and/or SD included paclitaxel, tacrolimus, carboxymethyl‐chitosan, β‐elemene, quercetin, plumbagin, erythromycin, budesonide, nintedanib, 5‐FU, TGF‐β1 antagonist, and mitomycin C.
TABLE 3.
Effect of pharmacological therapy on benign airway stenosis.
| Author (year) | Medicine | Relevant indictors | Evaluation methods | Outcome |
|---|---|---|---|---|
| Deng et al. (2023) [10] | Paclitaxel | SI %, SD %, and LP thickness | CT measurement | Paclitaxel partially reversed SI% and SD%, and decreased thickness of the LP |
| Lee et al. (2022) [17] | PT + BL | Width of stoma | H&E staining | PT combined BL has the potential to be an effective preventative treatment for tracheal stenosis |
| Mizokami et al. (2015) [11] | Tacrolimus | SD % | H&E staining | Low‐dose systemic tacrolimus has a preventive effect on laryngotracheal stenosis |
| Huang et al. (2023) [18] | CM‐chitosan | SD % | Endoscopic evaluation and CT | Inhalation of CM‐chitosan mitigated posttraumatic tracheal fibrosis in a rabbit model |
| Wei et al. (2020) [19] | Nintedanib/BUD | SI % | H&E staining | Nintedanib and BUD reduced tracheal stenosis and inflammation in tracheal tissue |
| Zhang et al. (2021) [13] | β‐elemene | SD % | H&E staining | β‐elemene attenuate granulation tissue hyperplasia, and ultimately alleviate airway scar stenosis |
| Xiao et al. (2021) [14] | Quercetin | SI % | H&E staining | Quercetin exhibits anti‐fibrotic activity and alleviates SD% |
| Tsai et al. (2021) [20] | Don | The LP thickness measurement and collagen formation | H&E staining | DON treatment significantly reduced the fibrotic LP thickness and collagen formation in iatrogenic laryngotracheal stenosis mice |
| Ertuğrul et al. (2007) [21] | Halofuginone | The fibrosis indexes | H&E staining | Systemically applied halofuginone hydrobromide decreases fibrosis/scar tissue formation |
| Ertuğrul et al. (2009) [22] | Halofuginone | The fibrosis indexes | H&E staining | Topically applied halofuginone hydrobromide decreases fibrosis/scar tissue formation |
| Duan et al. (2016) [23] | Tanshinone IIA | The LCR and the percent of fibrosis | H&E staining | Tanshinone IIA prevented tracheal narrowing, the LCR and the percent of fibrosis were smaller than the control groups |
| Olmos‐Zuñiga et al. (2017) [24] | Pirfenidone and collagen‐PVR | Inflammation and fibrosis | H&E staining | Pirfenidone and Collagen‐PVP decrease inflammation, fibrosis, TGF‐𝛽1 expression, and collagen deposition in the posttracheoplasty rats' scar |
| Shi et al. (2021) [15] | Plumbagin | The pathological alterations of the airway mucosa and SD % | H&E staining | Plumbagin regulates lung fibroblast activity and attenuates tracheal stenosis in rats |
| Huang et al. (2020) [25] | ERY/ERY + BUD | SD % | H&E staining | Erythromycin could alleviate SD% and improve the proliferation of mucosal epithelium |
| Qin et al. (2018) [26] | AMK/BUD/ERY/PEN/AMK + BUD/ERY + BUD/PEN + BUD | EPI and LP | H&E staining | The thickness in the ERY + BUD group was also significantly lower than that of the AMK + BUD or PEN + BUD groups |
| Mao et al. (2011) [27] | 5‐FU ethosomes | SI %, SD % | H&E staining | The mean SI and SD in 5‐FU ethosomes treatment was significantly declined at 21 days compared with simple 5‐FU treatment |
| Guven et al. (2011) [28] | Group 1: 5‐FU/TA; Group 2: carnitine; Group 3: DEX | The fibrotic tissue volumes | H&E staining | 5‐FU/TA and carnitine diminish the occurrence of tracheal stenosis (TS) secondary to experimentally induced tracheal trauma |
| Ingrams et al. (2000) [29] | 5‐FU and TA | SD % | Standard computer morphometric software | The results showed that the control group had a mean stenosis of 52%, whereas the treated group had a mean stenosis of 32% |
| Elizabeth et al. (2016) [30] | IL‐1RA anakinra | The LP thickness | H&E staining | The early use of the IL‐1R anakinra can prevent early granulation formation |
| Anton‐Pacheco et al. (2016) [31] | TGF‐β1 antagonist | SD % | H&E staining | TGF‐β1 antagonist therapy was not sufficient to improve tracheal narrowing |
| Simpson et al. (2008) [32] | Anti‐TGF‐β | SD % | H&E staining | In the canine model of induced subglottic airway injury, a combination of intralesional and intravenous anti‐TGF‐β results in a reduction in tracheal stenosis, and an increase in survival time |
| Çalik et al. (2020) [33] | Mitomycin‐C | Tracheal LD and SETT | H&E staining | Mitomycin‐C was more effective than saline for LD, SETT, inflammatory cells, and fibroblasts |
| Ekinci et al. (2017) [34] | Mitomycin‐C and simvastatin | Severity of inflammation, degree of fibrosis, width of tracheal lumen, maximal and minimal wall thickness | H&E staining | Simvastatin and Mitomycin‐C were not effective in preventing tracheal stenosis, inflammation and fibrosis formation |
| Eliashar et al. (1999) [35] | Mitomycin‐C and repeated Mitomycin‐C | SD % | H&E staining | A single topical treatment with low dose mitomycin partially prevents and significantly reduces the severity of surgically induced LTS in a canine model |
| Eliashar et al. (2004) [36] | Dilation combined Mitomycin | SD % | H&E staining | Mitomycin exerts a benefit equal to that of normal saline when applied to a well‐established laryngotracheal stenosis in dogs and does not prevent repeated stenosis after endoscopic dilation |
| Iñiguez‐Cuadra et al. (2008) [37] | Mitomycin | SD % | H&E staining | Topical mitomycin is not effective for avoiding tracheal stenosis and may provoke the opposite effect if the dose is not carefully selected |
| Kuzucuoğlu et al. (2019) [38] | Mitomycin‐C | Diameter and wall thickness of the tracheas | H&E staining | Topically applied mitomycin‐C following tracheal surgery slows down epithelization and, thus, decreases the development of granulation tissue and maintains a wider diameter of the trachea |
| Correa et al. (1999) [39] | Mitomycin‐C | The distance of stenosis and the mean relative collagen percentage | H&E staining | Mitomycin‐C favorably altered the clinical progression of subglottic stenosis, improved quantified airway patency, and reduced the amount of subglottic collagen formation in the canine model |
| Roh et al. (2006) [40] | Mitomycin‐C | The cross‐sectional area of subglottic lumen/Histologic grades of collagen deposition | H&E staining | The cross‐sectional area of subglottic lumen showed no difference among the mitomycin‐C treated and saline control groups/Histologic grades of collagen deposition in the submucosa of the posterior subglottis were lower in the mitomycin‐C treated groups than those in the wound control group |
| Cincik et al. (2005) [41] | Mitomycin‐C/5‐FU/TA | The thickness of the fibrotic areas/the fibrosis index | H&E staining | Both mitomycin‐C and 5‐FU/TA decrease fibrosis/scar tissue formation secondary to experimentally induced subglottic trauma in the rabbit model |
| Gezer et al. (2010) [42] | Tenoxicam | The scoring of inflammatory cell infiltration, angiogenesis, fibroblast proliferation, and collagen deposition. | H&E staining | Epithelial regeneration was higher, and fibroblast proliferation was lower in the tenoxicam group |
| Ghosh et al. (2013) [43] | DEX | The LP thickness | H&E staining | All specimens taken from steroid treated chemically and mechanically injured specimens showed both attenuated and regenerated epithelium with little to no evidence of granulation, with a marked absence of cellular infiltrate |
| Gonzalez et al. (1992) [44] | DEX | Minimum subglottic airway area in square millimeters | H&E staining | Aerosolized DEX preserves the subglottic airway area and decreases the clinical severity of airway obstruction in the acutely injured ferret larynx |
| Wistermayer et al. (2020) [45] | DEX | SD% | Endoscopic images | A single dose of intramuscular DEX given prior to a subglottic injury resulted in a statistically significant reduction in airway stenosis |
Abbreviations: 5‐FU, 5‐fluorouracil; AMK, amikacin; BL, blue light; BUD, budesonide; CM‐chitosan, carboxymethyl‐chitosan; DEX, dexamethasone; Don, 6‐Diazo‐5‐oxo‐l‐norleucine; EPI, thickness of the epithelium; ERY, erythromycin; H&E, hematoxylin and eosin; LCR, ration of the thickness of the lamina propria to the thickness of the cartilage; LD, lumen diameters; LP, lamina propria; PEN, penicillin; PT, phlorotannins; PVP, polyvinylpyrrolidone; SD, degree of tracheal stenosis; SETT, subepithelial tissue thickness; SI, stenosis index; TA, triamcinolone acetonide.
Another 24 animal studies assessed secondary outcomes, including LP thickness, stoma width, LCR, collagen formation, the fibrosis indexes, and inflammation severity (via H&E staining). Several agents have emerged as potential preventive treatments for tracheal stenosis, such as phlorotannins, DON, halofuginone, tanshinone IIA, pirfenidone, plumbagin, IL‐1RA (anakinra), mitomycin C, tenoxicam, and dexamethasone (DEX). Specifically, DON significantly reduced fibrotic LP thickness and collagen formation in a mouse model of iatrogenic laryngotracheal stenosis. Halofuginone hydrobromide (systemic or topical) also effectively diminished fibrosis and scar tissue formation. Tanshinone IIA prevented tracheal narrowing, with lower LCR and reduced fibrosis percentage versus controls. Moreover, a single intramuscular dose of DEX administered before subglottic injury led to a statistically significant reduction in airway obstruction.
3.5. The SI
As shown in Figure 3, the pooled WMD for SI was −0.21 (95% CI: −0.33 to −0.10, p < 0.001), indicating that pharmacological therapy was associated with a significant reduction in SI compared with the control group. Due to substantial heterogeneity (I 2 = 82%, p < 0.01), a random‐effects model was applied.
FIGURE 3.
Forest plot showing the effect of pharmacological therapy on SI.
3.6. The Degree of Tracheal Stenosis (SD)
As presented in Figure 4, the meta‐analysis demonstrated that pharmacological therapy was associated with a significant reduction in SD (pooled WMD = −0.26; 95% CI: −0.34 to −0.18; p < 0.001). Notably, significant heterogeneity was observed across studies (I 2 = 93%, p < 0.01), warranting the use of a random‐effects model.
FIGURE 4.
Forest plot showing the effect of pharmacological therapy on SD.
3.7. The Fibrosis Indexes
As shown in Figure 5, the pooled WMD for the fibrosis indexes was −3.15 (95% CI: −4.4 to −1.9, p < 0.001), indicating that pharmacological therapy was associated with a significant reduction in the fibrosis indexes compared with the control group. Due to substantial heterogeneity (I 2 = 82%, p < 0.01), a random‐effects model was applied.
FIGURE 5.
Forest plot showing the effect of pharmacological therapy on the fibrosis indexes.
3.8. Subgroup Analysis
We analyzed the source of heterogeneity by evaluating SD in a subgroup analysis (Supporting Information figures). Specifically, we focused on injury models (Figure S1), follow‐up duration (Figure S2), long‐term follow‐up (Figure S3), and mitomycin therapy (Figure S4). For mechanical injury models and follow‐up durations of less than 14 days, the pooled WMDs with 95% confidence intervals (CIs) were −0.22 (−0.31 to −0.13), I 2 = 81%, and −0.24 (−0.36 to −0.13), I 2 = 45%, respectively (p < 0.01). Regarding long‐term follow‐up (> 14 days), the pooled WMD (95% CI) was −0.26 (−0.36 to −0.16), I 2 = 93% (p < 0.01). The pooled WMD (95% CI) for mitomycin therapy was −0.40 (−0.53 to −0.27), I 2 = 64%.
3.9. Sensitivity Analyses
Sensitivity analyses were performed using “one‐study‐removed” analyses. We used sensitivity analyses to evaluate whether the pooled effect size still fell within the total pooled effect size of the 95% CI, indicating that the outcomes of the meta‐analysis were stable.
3.10. Publication Bias
Funnel plots were used to assess publication bias in SI, SD, and the fibrosis indexes individually (Supporting Information figures). The funnel plot showed publication bias in SI (Figure S5), SD (Figure S6), and the fibrosis indexes (Figure S7).
3.11. DAG
Pharmacological agents alleviate airway stenosis by inhibiting fibroblast activity through multiple mechanisms. These include suppressing fibroblast proliferation, migration, and invasion, reducing the expression of fibrotic phenotypic markers, and ameliorating excessive collagen accumulation and fibrogenesis. Additionally, these agents exert anti‐inflammatory effects, downregulate extracellular matrix proteins, and modulate key signaling pathways such as Smad2/3, ERK, and p38, thereby interfering with both Smad and non‐Smad signaling cascade (Figure S8).
4. Discussion
Benign tracheal stenosis is a rare and serious disease that poses a considerable threat to human health. It is well established that granulation hyperplasia exerts an essential role in the pathogenesis of tracheal stenosis. Once it occurs, this condition can substantially impact the quality of life for patients. Although numerous studies have demonstrated that interventional bronchoscopy can ameliorate dyspnea symptoms and provide temporary relief from airway obstruction in patients with airway stenosis, the long‐term prognostic improvement remains limited. Due to the lack of effective treatments, the mortality rate associated with this condition is significantly high. Hence, it is essential to investigate low‐cost drugs with high efficacy. In the present study, we conducted a meta‐analysis of the literature to assess the effectiveness of various pharmacological therapies in animal models of tracheal stenosis, which may offer an effective preventative treatment for this disease.
The evidence for our meta‐analysis was derived from 34 animal studies, which collectively involved a total of 873 animals, including rabbits, rats, mice, mongrel dogs, and ferrets. The agents paclitaxel, tacrolimus, carboxymethyl‐chitosan, β‐elemene, quercetin, plumbagin, erythromycin, budesonide, nintedanib, 5‐fluorouracil, TGF‐β1 antagonist, and mitomycin C exhibit the potential to mitigate SI and SD associated with tracheal stenosis. Previous research indicated that paclitaxel inhibits tracheal scar formation by suppressing the proliferation of human tracheal fibroblasts and inducing cell apoptosis [46]. In this research conducted by Deng et al., it was found that POCUS‐guide submucosal injection of paclitaxel could reverse collagen deposition and alleviate tracheal stenosis [10]. The primary causes of tracheal stenosis were identified as granulation tissue formation and fibrosis. Lee et al. reported that phlorotannins‐combined blue light significantly reduced the expression levels of collagen and extracellular matrix protein, thereby preventing the progression of tracheal stenosis [17]. Furthermore, Mizokami et al. demonstrated that low‐dose systemic tacrolimus exerts a preventive effect on laryngotracheal stenosis by inhibiting the activation of immune cells within the airway mucosa during the early stages of wound healing [11]. The abovementioned findings are based on short‐term observations, thus necessitating further long‐term study.
Various methodologies have been developed for inducing experimental models of trachea‐related injuries, including mechanical injury, electrocautery, surgical injury, and chemical intervention. These approaches ultimately lead to fibroblast proliferation and differentiation accompanied by granulation hyperplasia. In our meta‐analysis, the majority of researchers employed rabbit models subjected to mechanical injury to establish tracheal stenosis. Nintedanib is a crucial therapeutic agent targeting pulmonary fibrosis. However, no clinical trials have yet documented its efficacy in patients suffering from benign forms specifically related to acquired conditions. The study conducted by Wei et al. illustrated that nintedanib alleviates tracheal stenosis in rabbits through processes associated with fibrotic developments [19]. Moreover, β‐elemene is widely recognized as an anticancer adjuvant due to its ability to enhance the effects of various anticancer drugs while exhibiting minimal toxicity [47]. Zhang et al. noted beneficial outcomes stemming from β‐elemene's capacity to inhibit excessive growths linked directly toward benign airway constrictions [13]. Another investigation highlighted quercetin's properties achieved through the inhibition of profibrogenesis factors via AKT/mTOR signaling pathways activation and autophagic activities [14]. Furthermore, two separate analyses revealed that erythromycin alone or erythromycin combined with other drugs could reduce collagen expression; it could effectively relieve resultant traumas inflicted upon affected areas following injurious events [25, 26]. Collectively, these findings provide experimental evidence supporting the clinical application of multiple drugs in the treatment of tracheal stenosis. Further inquiries are necessary to elucidate whether these agents may play crucial roles concerning future clinical implementations.
More recently, mitomycin C has garnered significant attention as an adjuvant therapy for tracheal stenosis. This meta‐analysis encompasses nine studies evaluating the efficacy of mitomycin C in treating tracheal stenosis; however, its effectiveness in preventing tracheal stenosis and reducing granulation tissue formation remains controversial. Eight animal studies showed that mitomycin C serves as an effective and safe adjuvant treatment within endoscopic management protocols for tracheal stenosis. Conversely, Iñiguez‐Cuadra et al. reported that topical mitomycin may not be effective in preventing tracheal stenosis and could potentially provoke adverse effects if dosages are not strictly selected [37]. The abovementioned findings regarding mitomycin C primarily derive from animal studies and do not comprehensively encapsulate its true efficacy. To our knowledge, several clinical trials have been undertaken to investigate the potential benefits of mitomycin C for patients with tracheal stenosis. Cataneo et al. reported that the topical application of mitomycin C is a treatment option for patients who cannot undergo surgery and those with postsurgical restenosis [48]. However, a focused clinical review conducted by Felice reviewed 29 studies and suggested that the efficacy of mitomycin C in reducing stenosis recurrence remains a matter of debate [12]. In addition, TGF‐β1 antagonists showed opposite outcomes in alleviating airway stenosis. In summary, the quality of evidence supporting mitomycin C and TGF‐β1 antagonist interventions was low, and the recommendation was weak. Therefore, there is a pressing need for higher‐quality and more rigorous clinical trials to validate the efficacy of mitomycin C and TGF‐β1 antagonist.
Furthermore, this meta‐analysis identified don, halofuginone, tanshinone IIA, pirfenidone, plumbgin, IL‐1RA anakinra, tenoxicam, and DEX as potential effective preventative treatments against tracheal stenosis. These investigations evaluated treatment effects through metrics such as LP thickness, width of stoma, LCR, collagen formation, the fibrosis indexes along with the severity of inflammation via hematoxylin and eosin staining techniques. While the quality of evidence from these studies is inadequate, they nonetheless offer new insights into future therapeutic approaches.
The SYRCLE Risk of Bias tool was utilized to evaluate the efficacy of various pharmacological agents. In this meta‐analysis, none of 34 articles met all 10 criteria indicative of low bias risk status; only two studies described random sequence generation. Although most studies endeavored to avoid different forms of bias, few researchers provided their protocols for scrutiny. This meta‐analysis reveals common methodological flaws in the existing literature and emphasizes the urgent need for greater methodological rigor. According to the GRADE assessment, the certainty of evidence was very low for the primary outcomes (SI and SD) as well as for the secondary outcomes (fibrosis indexes).
This study acknowledges several limitations. Firstly, the pharmacological agents examined predominantly stem from animal studies, which do not provide a comprehensive assessment of their true efficacy in a clinical setting. Secondly, most investigations are based on short‐term observations, highlighting the need for further long‐term study. Thirdly, many studies were conducted only once with a limited sample size; thus, additional large‐animal studies are warranted. Fourth, funnel plots revealed evidence of publication bias in this meta‐analysis. As expected, studies reporting positive results are more likely to be published, particularly in animal research. Despite these limitations, our research contributes valuable insights into prospective therapeutic strategies.
5. Conclusion
This meta‐analysis encompassed 34 articles involving a total of 873 animals and suggests that various pharmacological agents may be beneficial for treating tracheal stenosis. However, these findings should be interpreted with caution due to the very low certainty of evidence, high heterogeneity, and potential publication bias observed. However, for clinical application, further in vivo studies are essential to determine the optimal timing and frequency of treatment, as well as to verify both the therapeutic effects and potential side effects associated with prolonged clinical use.
Funding
Dengyuan Li and Jie Zeng report that financial support was provided by The Joint Application Foundation Project of Kunming Medical University and Yunnan Provincial Science and Technology Department (202101AY070001‐271), Basic Research Project of Yunan Provincial Science and Technology Department (202401AT070055), and Yunnan Provincial Medical Discipline Reserve Talent Program (H‐2025026), respectively.
Ethics Statement
The authors have nothing to report.
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1: Forest plot summarizing the relationship between injury model and SD.
Figure S2: Forest plot summarizing the relationship between follow‐up duration and SD.
Figure S3: Forest plot summarizing the relationship between long‐term follow‐up and SD.
Figure S4: Forest plot summarizing the relationship between mitomycin therapy and SD.
Figure S5: Funnel plots for SI.
Figure S6: Funnel plots for SD.
Figure S7: Funnel plots for the fibrosis indexes.
Figure S8: Directed acyclic graph (DAG) of pharmacological agents for alleviating airway stenosis.
Table S1: PRISMA 2009 checklist.
Table S2: The detail search strategy.
Acknowledgments
AI was used solely for language polishing and grammar checking. No AI was used for data analysis, interpretation, or content generation.
Data Availability Statement
All supporting data are included in this article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Forest plot summarizing the relationship between injury model and SD.
Figure S2: Forest plot summarizing the relationship between follow‐up duration and SD.
Figure S3: Forest plot summarizing the relationship between long‐term follow‐up and SD.
Figure S4: Forest plot summarizing the relationship between mitomycin therapy and SD.
Figure S5: Funnel plots for SI.
Figure S6: Funnel plots for SD.
Figure S7: Funnel plots for the fibrosis indexes.
Figure S8: Directed acyclic graph (DAG) of pharmacological agents for alleviating airway stenosis.
Table S1: PRISMA 2009 checklist.
Table S2: The detail search strategy.
Data Availability Statement
All supporting data are included in this article.