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. 2025 Mar 5;211(5):803–813. doi: 10.1164/rccm.202407-1325OC

Select Airway Specialized Proresolving Mediators Are Associated with Recovery from Nonviral Chronic Obstructive Pulmonary Disease Exacerbations

Lydia J Finney 1,✉, Jordina Mah 1, Melody Duvall 2,3, Dexter Wiseman 1, Faisal Kamal 1, Peter Fenwick 1, Andrew I Ritchie 1, Tata Kebadze 1, Christopher Orton 1,4, Pankaj Bhavsar 1, James P Allinson 1,4, Mairi Macleod 1, Alexander J Mackay 1, Federico Baraldi 1,5, Samuel Kemp 6, Aran Singanayagam 1, Sebastian L Johnston 1, Adam J Byrne 1,7, Bruce D Levy 2,*, Jadwiga A Wedzicha 1,*
PMCID: PMC12091024  PMID: 40043205

Abstract

Rationale

Recovery from chronic obstructive pulmonary disease (COPD) exacerbations is heterogeneous and has a profound impact on disease trajectories. Resolution of airway inflammation is an active process that may be driven by specialized proresolving mediators (SPMs).

Objectives

We sought to characterize the temporal change in SPMs in the sputum of patients with COPD during exacerbations, their association with exacerbation triggers, and exacerbation recovery.

Methods

Participants were recruited from the London COPD Exacerbation Cohort between January 11, 2016, and April 30, 2018. Participants were reviewed at baseline, exacerbation onset, 1 week, 2 weeks, and 6 weeks during their exacerbation recovery. Sputum collection, nasopharyngeal swabs, phlebotomy, quality-of-life questionnaires, and spirometry were performed at each visit. SPMs were measured in sputum by liquid chromatography–tandem mass spectrometry. Respiratory viruses were measured by quantitative PCR and bacteria by microbiological culture.

Measurements and Main Results

There were 68 exacerbations during the study period. Median time to symptomatic recovery was 21 days for viral exacerbations, compared with 13 days in nonviral exacerbations (P < 0.001). There was a significant increase in resolvin D1 (RvD1) at exacerbation onset in bacterial exacerbations but not in viral exacerbations. Lower levels of RvD1 were associated with prolonged respiratory symptoms during the 1-week and 2-week recovery time points. Exogenous RvD1 significantly reduced IL-6 and CXCL8 response to rhinovirus infection in COPD bronchial epithelial cells.

Conclusions

There is a dynamic temporal change in airway SPMs during COPD exacerbations. Reduced levels of RvD1 were associated with prolonged respiratory symptoms. SPMs may be a potential therapeutic approach to promote exacerbation recovery.

Keywords: COPD, exacerbations, specialized pro-resolving mediators, viruses, recovery

At a Glance Commentary

Scientific Knowledge on the Subject

Recovery from chronic obstructive pulmonary disease exacerbations is heterogenous and has a significant impact on disease trajectories.

What This Study Adds to the Field

Specific sputum specialized proresolving mediators were associated with different pathogens and with time to exacerbation recovery in chronic obstructive pulmonary disease. Resolvin D1 reduced inflammatory response to viral infection in vitro.

Exacerbations are important events in the life of people with chronic obstructive pulmonary disease (COPD). They are the main cause of hospital admissions and death in COPD (1–4), with frequent exacerbations being associated with rapid lung function decline and impaired quality of life (5, 6). Exacerbations are commonly triggered by respiratory viruses or changes in the airway microbiome (7–10), with air pollution being increasingly recognized as a noninfectious trigger (11–13). Although exacerbation triggers are varied, trajectories of exacerbation recovery are also heterogeneous. The COPDGene study investigators previously reported that the most significant loss of lung function with exacerbations was seen in patients with COPD and in smokers with mild disease (14). Donaldson and colleagues found that 7.3% of patients with COPD did not recover their lung function at 3 months after a moderate COPD exacerbation, with non-ecovery resulting in more rapid disease progression compared with those who do recover (15). In addition, viral exacerbations are associated with prolonged respiratory symptoms, compared with exacerbations where no virus is detected (16), with delayed exacerbation recovery being associated with persistent airway inflammation at 1 week after exacerbation onset (17). Human COPD rhinovirus challenge studies also indicate that symptomatic and inflammatory recovery can take weeks in some individuals (18).

Resolution of inflammation after an infection is an active process with a profound impact on disease outcomes across a range of inflammatory diseases (19). Specialized proresolving mediators (SPMs) are lipid mediators derived from dietary essential fatty acids, including docosahexaenoic acid (DHA), eicosapentaenoic acid, and arachidonic acid (19). SPMs promote resolution of sterile and infectious inflammation by counterregulation of proinflammatory cytokine signaling, promoting efferocytosis and host defense mechanisms and inhibiting further neutrophil inflammatory cell influx, leading to a return to homeostasis (20–22).

The aim of this study was to investigate the temporal change in airway SPMs by determining their levels in the sputum of patients with COPD during exacerbations, their association with different exacerbation triggers, and their relationship to the duration of exacerbation recovery. We hypothesized that the more prolonged viral exacerbations would be associated with lower levels of sputum SPMs at exacerbation onset compared with faster resolving bacterial exacerbations and that lower levels of sputum SPMs at exacerbation would be associated with prolonged respiratory symptoms.

Methods

Participants were recruited from the London COPD Exacerbation Cohort (23). The protocol was approved by the Hampstead Research Ethics Committee (no. 09/H0720). All participants gave written informed consent and had a diagnosis of COPD based on an FEV1/FVC ratio of less than 0.70 on spirometry performed according to American Thoracic Society and European Respiratory Society guidelines (24). (For full inclusion and exclusion criteria, see the online supplement.) Participants kept daily diary cards of symptoms as previously described and were trained to report symptoms of an exacerbation to the study team (16). Participants were seen within 48 hours of reporting an exacerbation before any treatment with antibiotics or oral corticosteroids. Participants were reviewed at baseline; at exacerbation onset; and during recovery at 1 week, 2 weeks, and 6 weeks after exacerbation onset. A clinical assessment included spirometry, COPD Assessment Test (CAT) score (25), spontaneous sputum collection, phlebotomy, and nasopharyngeal (NP) swabs at each visit. Exacerbation duration was defined by the duration of additional respiratory symptoms above baseline symptoms as documented on participants’ diary cards. The start of an exacerbation was defined as the first day of 2 consecutive days of two or more respiratory symptoms compared with baseline as previously described (15–17). The end of an exacerbation was defined as the first day of 2 or more consecutive days with no additional respiratory symptoms (15–17). Bacterial infection was identified by standard sputum microbiological culture. Serum and sputum were processed as previously described before storing at −80°C for further analysis (23). Respiratory viruses were detected in sputum and NP swabs by quantitative PCR (26).

SPMs were measured in sputum supernatants by liquid chromatography– tandem mass spectrometry (LC-MS/MS; Ambiotis) (see Figure E1 in the online supplement). In addition, to further evaluate the relationship between resolvin D1 (7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E, 19Z-docosahexaenoic acid [RvD1]) and a range of clinical parameters, RvD1 (Figure 1) was also measured in sputum supernatants by ELISA (Cayman Chemicals; catalog no. CAY500380) according to the manufacturer’s instructions. Sputum myeloperoxidase (MPO) was measured by ELISA (R&D Systems; catalog no. DY3174).

Figure 1.

Figure 1.

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Chemical structure and biosynthetic pathway for resolvin D1. (A) Chemical structure of resolvin D1 (7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid). (B) Resolvin D1 is derived from dietary docosahexaenoic acid (DHA), which is catalyzed by 15-lipoxygenase (A15LOX), which can be found in epithelial cells to the oxidized lipid 17S-H(p)DHA (HDHA). This is converted by ALOX5 in peripheral blood mononuclear cells to its 7,8 epoxide intermediate. Enzymatic hydrolysis of the epoxide intermediate leads to the bioactive specialized proresolving mediator resolvin D1.

Bronchial Epithelial Cell (BEC) Experiments

We obtained BECs with bronchial brushings from participants with COPD from the London COPD Exacerbation Cohort and age-matched healthy controls. All participants gave written informed consent, and the protocol was approved by the Bromley Research Ethics Committee (no. 15/LO/1241). BECs at Passage 2 were grown on collagen (PureCol Advanced Biomatrix; catalog number 5005)-coated 24-well plates to submerged culture in PromoCell media until 80% confluent. BECs were infected with rhinovirus 16 (RV-16) at a multiplicity of infection of 1 for 1 hour on a rocker. BECs were treated with 1 nM RvD1 in 0.004% ethanol or vehicle (ethanol, 0.004%) for 30 minutes before RV infection, 1 hour after RV infection, and 24 hours postinfection. Supernatants were removed at 0, 6, 24, 48, and 72 hours. Inflammatory mediators CXCL8, IL-6, IL-1β, IL-10, and interferons IFN-α2α, IFN-β, IFN-γ, and IFN-λ/IL-29 were measured with the U-PLEX assay (Meso Scale Discovery) according to the manufacturer’s instructions (for the lower limit of detection, see Table E1). RNA was extracted from cell lysates using the QIAGEN Mini Kit (catalog number 74106) as in the study by Singanayagam and colleagues (26). RV viral load, Myxovirus resistance protein, oligoadenylate synthetase, Viperin, 18S, and arachidonate 15-lipoxygenase (ALOX15) (ThermoFisher; catalog number 4331182) were measured by quantitative PCR Taqman assay as previously reported (27) (for primers and probes, see Table E2).

To investigate the effect of RvD1 on bacterial infection, BECs were infected with heat-killed nontypeable Haemophilus influenzae (NCTC1479) at 1.5 × 1010 colony-forming units. BECs were treated with 1 nM RvD1 in 0.004% ethanol or vehicle (ethanol, 0.004%) for 30 minutes and 1 hour postinfection. Inflammatory mediators CXCL-8 and IL-6 were measured with ELISA. ALOX15 and 18S were measured by quantitative PCR.

Statistical analysis was performed using GraphPad PRISM, Version 9. All data were assessed for normality. Nonparametric repeated measures data were analyzed using the Friedman test with Dunn’s post hoc test for multiple comparisons. We performed nonparametric unpaired analyses using multiple Mann-Whitney U tests with the Bonferroni-Dunn method for multiple comparisons. Multivariable data were corrected using the Benjamini-Hochberg correction for multiple comparisons.

Results

Participant Demographics

There were 68 reported acute exacerbations of COPD (AECOPD) in 65 patients between January 11, 2016, and April 30, 2018 where a viral NP swab and spontaneous sputum were available. RV was detected in 31 (45.6%) AECOPD, with respiratory syncytial virus (RSV) being detected in 2 (3%) AECOPD and influenza B in 1 (1.5%) AECOPD. No virus was detected in 34 exacerbations (50%). There were 10 (29.4%) nonviral exacerbations where potentially pathogenic bacteria were isolated in sputum. Because of the predominance of RV as a cause of viral exacerbations, other causes of viral exacerbations were excluded from further analysis. The median age of participants was 69 (interquartile range [IQR] = 64–72). They were 65% male, with 24.6% being current smokers. Participants had a median of 2 (IQR = 1–2.75) exacerbations in the previous year. The median baseline CAT score was 17.5 (IQR = 13–23), with 58.5% being prescribed triple inhaled therapy (combined inhaled corticosteroid, long-acting antimuscarinic, and long-acting β agonist). There were 10 patients who took aspirin (15.4%). Participants with nonviral exacerbations had a significantly higher median baseline CAT score of 19 (IQR=15.5–30), whereas participants with RV exacerbations had a median CAT score of 15 (IQR=10–22) in univariate analysis (P = 0.013), but this was not significant after adjustment for multiple comparisons (Table 1). There was no other significant difference in baseline demographics between patients who had nonviral exacerbations and those who had RV-positive exacerbations.

Table 1.

Demographic Data for London COPD Cohort Participants

Baseline Demographic Total (N = 65) Nonviral (n = 34) Rhinovirus (n = 31) P Value for Nonviral vs. Viral
Age, median (IQR) 69 (66–76) 69 (64–72) 72 (68–77) 0.12
Male, n (%) 42 (65) 19 (74) 23 (56) 0.19
FEV1, L 1.31 (0.96–1.76) 1.20 (0.93–1.69) 1.39 (0.99–2.09) 0.13
Exacerbations previous year, median (IQR) 2 (1–2.75) 2 (1–2.5) 2 (1–3) 0.69
CAT, median (IQR) 17.5 (13–23) 19 (15.5–30) 15 (10–22) 0.01
Current smoker, n (%) 16 (24.6) 8 (23.5) 8 (25.8) 0.78
Inhaled corticosteroid use, n (%) 48 (73.8) 25 (73.5) 23 (74.2) >0.99
LABA use, n (%) 49 (75.4) 25 (73.5) 24 (77.42) 0.78
LAMA use, n (%) 47 (72.3) 22 (64.7) 25 (80.7) 0.18
Triple therapy, n (%) 38 (58.5) 17 (50.0) 22 (71.0) 0.13
Aspirin once daily, n (%) 10 (15.4) 4 (12.9) 5 (14.7) >0.99
Ethnicity, n (%)
 White 60 (92.3) 30 (88.0) 30 (96.7) —
 Black 0 (0) 0 (0) 0 (0) —
 Asian 2 (3.1) 2 (6.6) 0 (0) —
 Mixed ethnic backgrounds 3 (4.6) 2 (6.6) 1 (3.3) —
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Definition of abbreviations: CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; IQR = interquartile range.

Clinical Characteristics of Exacerbations and Exacerbation Recovery

At exacerbation onset, there were no significant differences in markers of severity by percent change in FEV1, change in CAT score, or C-reactive protein levels between RV and nonviral exacerbations (see Table E3). However, in this data set, blood eosinophil count was higher in nonviral exacerbations, compared with viral exacerbations, at exacerbation onset (Table E3). All participants were seen before starting treatment. Participants with a nonviral exacerbation were more likely to go on to receive antibiotics than participants who had viral exacerbations (97% vs. 75%; P = 0.013), but there was no difference in oral corticosteroid treatment (73% vs. 56%; P = 0.43).

Participants with RV-triggered exacerbations had a median exacerbation duration of 21 days and took significantly longer to recover symptomatically, as indicated by diary card documentation, compared with nonviral exacerbations with a median duration of 13 days (χ2 = 16.62, P < 0.001; log-rank Mantel-Cox test) (Figure 2A). At the 2-week follow-up visit, 81% of participants with RV exacerbations had a CAT score of 2 or more points (minimum significant difference) from baseline, compared with 50% of nonviral exacerbations (P = 0.038) (Figure 2B). Participants with RV exacerbations also had a persistently decreased FEV1 percent change from baseline of −10.3% (IQR = −4.8–13.5) at 2 weeks after exacerbation onset, compared with −3.7% (IQR = −8.3–1.8) for nonviral exacerbations (P = 0.019) (Figure 2C). There was no difference in other clinical markers of severity at 2 weeks (see Table E4), but blood eosinophil count and neutrophil count were higher in the nonviral group compared with viral exacerbations at 6 weeks (see Table E5).

Figure 2.

Figure 2.

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Clinical parameters of exacerbation recovery in viral and nonviral exacerbations of chronic obstructive pulmonary disease. Participants from the London COPD Exacerbation Cohort kept daily diary cards of respiratory symptoms. (A) Symptomatic recovery was defined as the cessation of additional respiratory symptoms above baseline as recorded on diary cards. Rhinovirus (RV) exacerbations were associated with prolonged respiratory symptoms as recorded on diary cards compared with nonviral exacerbations (P < 0.001; log-rank Mantel-Cox test). (B) At the 2-week visit, 81% of participants with RV exacerbations had a CAT score of 2 or more points (minimum significant difference) from baseline compared with 50% of nonviral exacerbations (P = 0.038; two-way ANOVA with Sidak’s multiple comparisons test. (C) There was a greater decrease in FEV1 percent change from baseline in RV exacerbations compared with nonviral exacerbations at 2 weeks. CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease. *P < 0.05.

The Effect of Bacterial Infection on Exacerbation Recovery in Viral and Nonviral Exacerbations

Bacteria were detected by microbiological culture in 20 (30.8%) exacerbations at exacerbation onset. There was no significant difference in the number of exacerbations with positive bacterial culture between nonviral (32.3%) and RV (29.4%) exacerbations at exacerbation onset (see Table E6). There was also no significant difference in the number of exacerbations with a positive bacterial culture between RV-positive and nonviral exacerbations at the 2-week recovery time point with 8.3% of nonviral and 25% of RV exacerbations being bacterial sputum culture–positive at 2 weeks. The detection of bacteria in sputum at 2 weeks was not associated with prolonged time to recovery or a greater decline in lung function at 2 weeks in this cohort (Figure E2).

Specialized Proresolving Mediators, Pathogens, and Recovery

SPMs have been shown to promote resolution of inflammation after both viral and bacterial infection in animal models (28–31). To determine whether there was a temporal change in the SPMs in the airways of patients with COPD during an exacerbation, SPMs were measured by LC-MS/MS in the sputum of eight exacerbations that were culture positive for bacteria at exacerbation onset and eight exacerbations that were RV positive at exacerbation onset. To form distinct groups where one pathogenic organism had been identified, exacerbations chosen where there was no coinfection with bacteria and a complete series of sputum samples for each time point were available. There were no differences in baseline demographics between patients with bacterial or viral exacerbations (see Table E7). At exacerbation onset, there was a significant increase in RvD1 compared with baseline in bacterial (67.3 pg/ml at exacerbation vs. 7.3 pg/ml at baseline; P = 0.008) but not viral exacerbations (20.7 pg/ml vs. 10.1 pg/ml; P value was not significant [ns]) (Figure 3A). At exacerbation onset, sputum RvD1 was significantly higher in bacterial exacerbations compared with viral exacerbations (67.3 pg/ml with bacteria vs. 10.1 pg/ml with virus; P = 0.015) (Figure 3A). At exacerbation onset, sputum RvE1 also increased significantly from baseline in bacterial exacerbations (1,018.3 pg/ml with exacerbation vs. 178.5 pg/ml at baseline), but not viral exacerbations (35.7 pg/ml vs. 103.1 pg/ml, ns), and was significantly greater in bacterial exacerbations at onset when compared with viral exacerbations (1,018.3 pg/ml with bacteria vs. 35.7 pg/ml with virus; P = 0.008) (Figure 3B). In contrast, there was an increase in other DHA-derived SPMs, namely Protectin D1 (PD1) and Maresin 2 (MaR2) at the 2-week recovery time point in viral, but not bacterial, exacerbations; however this did not reach significance (see Figures E3 and E4).

Figure 3.

Figure 3.

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Chronic obstructive pulmonary disease exacerbations are associated with a temporal dynamic change in sputum specialized proresolving mediators. Specialized proresolving mediators were measured in sputum by liquid chromatography–tandem mass spectrometry. Resolvin D1 (RvD1) significantly increased at exacerbation onset (Exac) in bacterial exacerbations but not viral exacerbations (n = 8). (A) RvD1 was significantly greater at exacerbation in bacterial compared with viral exacerbations. (B) Resolvin E1 (RvE1) significantly increased in bacterial exacerbations but not viral exacerbations. However, there was not a significant difference in RvE1 between viral and bacterial exacerbations at exacerbation onset. *P < 0.05 difference between groups, #P < 0.05, ##P < 0.01 difference in time points.

To investigate whether lower levels of sputum RvD1 were associated with prolonged exacerbation symptoms, RvD1 was measured in sputum using LC-MS/MS at baseline, exacerbation onset, and 2-week recovery. Symptom duration was calculated from diary cards as described in the Methods section. There was no relationship between sputum RvD1 at baseline and the duration of exacerbation symptoms. Likewise, there was no relationship between sputum RvD1 at exacerbation onset and exacerbation symptom duration (Figures 4A and 4B). In contrast, there was an inverse relationship between exacerbation symptom duration and sputum RvD1 levels at the 2-week recovery visit (ρ = −0.677; P = 0.009), indicating that lower levels of RvD1 during exacerbation recovery were associated with prolonged symptoms (Figure 4C). There was no significant relationship between sputum RvD1 or RvE1 and change in FEV1 during recovery (see Figure E5).

Figure 4.

Figure 4.

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Reduced levels of sputum resolvin D1 (RvD1) are associated with delayed recovery from exacerbations of chronic obstructive pulmonary disease. RvD1 was measured in sputum by liquid chromatography–tandem mass spectrometry (LC-MS/MS). (A and B) At (A) symptomatic baseline and (B) exacerbation onset, there was no relationship between RvD1 and exacerbation symptom duration. (C) However, at 2 weeks after exacerbation onset, lower levels of sputum RvD1 were associated with prolonged exacerbation symptoms. (D) There was a good correlation between sputum RvD1 measured by ELISA and by LC-MS/MS.

To investigate the relationship between RvD1 and clinical parameters, we measured sputum RvD1 levels by ELISA in multiple additional samples. For validation of the immunoreactive RvD1 levels, biospecimens for which LC-MS/MS analyses were performed were also subject to ELISA for quantitation. There was excellent agreement between paired RvD1 levels measured by LC-MS/MS and ELISA methodology (ρ = 0.861; P < 0.001) (Figure 4D). RvD1 induction was determined according to bacterial species isolated at exacerbation onset. The most common bacteria identified at exacerbation were Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Pseudomonas aeruginosa (Table E6). There was no significant difference in RvD1 levels at exacerbation according to bacterial species detected (see Figure E6). Similarly, there was no significant difference between RvD1 levels in RV-positive exacerbations compared with RSV- or influenza-positive exacerbations (Figure E6).

Sputum RvD1, Neutrophil Activation, and Proinflammatory Mediators

Having identified an association between ongoing symptoms and levels of RvD1 in sputum (Figure 4), we measured the relationship between sputum inflammatory mediators and RvD1 in sputum at exacerbation onset, 1 week, 2 weeks, and 6 weeks after exacerbation onset. There was no significant correlation between RvD1 and sputum inflammatory markers or makers of neutrophil activation at exacerbation onset (see Figure E7). RvD1 was positively associated with CXCL10 at 1 week after exacerbation onset (ρ = 0.537; P = 0.03 (Figure 5A), with IL-6 (ρ = 0.736; P = 0.006) and MPO (ρ = 0.649; P = 0.02) at 2 weeks after exacerbation onset (Figures 5B and 5C); and with CXCL8 at the 6-week recovery time point (ρ = 0.642; P = 0.037) (Figure 5D).

Figure 5.

Figure 5.

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The relationship between resolvin D1 (RvD1) and proinflammatory mediators changes during the time course of a chronic obstructive pulmonary disease exacerbation. RvD1 was measured in sputum by ELISA. Proinflammatory mediators were measured using the U-PLEX assay platform (Meso Scale Discovery). (A) At 1 week after exacerbation onset, RvD1 positively correlated with CXCL10. (B and C) At 2 weeks, there was a positive relationship (B) between RvD1 and IL-6 and (C) between RvD1 and myeloperoxidase. (D) At 6 weeks, there was a positive relationship between RvD1 and CXCL8.

RvD1 Reduces Inflammatory Cytokine Response to RV Infection in BECs

Given the significant association between sputum RvD1, IL-6, and CXCL8 (Figures 5B and 5C), we next performed a series of experiments to determine the impact of RvD1 on airway epithelial IL-6 production. BECs from participants with COPD (n = 10) and age-matched healthy controls (n = 6) were infected with RV and incubated with RvD1 or vehicle, and inflammatory cytokines were measured in cell supernatant aliquots with the Meso-Scale-Discovery U-Plex (see the Methods section). (For demographic data, see Table E8.) In RV-infected COPD BECs, exposure to RvD1 (1 nM) was associated with a significant reduction in IL-6 levels (167.8 pg/ml with RvD1 vs. 592 pg/ml with vehicle control; P = 0.009) at the 24-hour time point, with a similar reduction in CXCL8 at 24 hours (777.7 pg/ml with RvD1 vs. 1,967.6 pg/ml with vehicle control; P = 0.029). There was no significant effect for RvD1 on IL-1β release after RV infection (Figure 6). RvD1 did not significantly effect interferon responses to RV infection in COPD BECs (Figure 6), and exposure to RvD1 did not significantly reduce viral load or expression of the IFN-stimulated genes Myxovirus resistance protein, Viperin, and oligoadenylate synthetase (see Figure E8). There was no significant effect of RvD1 on inflammatory cytokine release in healthy BECs (see Figure E9).

Figure 6.

Figure 6.

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Resolvin D1 (RvD1) reduces the IL-6 response to rhinovirus infection in bronchial epithelial cells (BECs) from donors with chronic obstructive pulmonary disease (COPD). BECs from donors with COPD were infected with rhinovirus 16 at Time 0. COPD BECs were pretreated at 30 minutes before infection, 30 minutes postinfection, and 24 hours postinfection with 1 nM RvD1 or 1 nM vehicle. Pro-inflammatory cytokines (A) IL-6, (B) IFN-beta, (C) CXCL8, (D) IFN-gamma, (E) IL-1beta and interferons, and (F) IL-29/IFN-lamda were measured in cell culture supernatants with the U-PLEX assay platform (Meso Scale Discovery). *P < 0.05.

RvD1 Reduces the Inflammatory Cytokine Response to Haemophilus influenzae Infection in COPD BECs

To further investigate the antiinflammatory effect of RvD1 on bacterial infection in COPD, BECs from participants with COPD (n = 6) were infected with H. influenzae and incubated with RvD1 or vehicle. Inflammatory cytokines were measured in cell supernatants by ELISA. In H. influenzae–infected BECs, RvD1 (1 nM) was associated with a 0.92-fold change in IL-6 versus a 1.89-fold change in vehicle control at 24 hours (P = 0.03) (see Figure E10). RvD1 had no significant effect on CXCL8 response to H. influenzae (Figure E10).

ALOX15 Gene Expression Is Reduced in BECs from Patients with COPD compared with Healthy Controls

To investigate whether a failure in SPM production during viral infection could be due to reduced synthesis of RvD1, expression of ALOX15 was measured in cell lysates from COPD BECs and healthy BECs infected with RV. There was significantly lower relative expression of ALOX15 in uninfected COPD BECs (log2 × 0.8 n = 8) compared with healthy BECs (log2 × 3.7; n = 5), P = 0.002 (Figure 7A). RV infection was associated with a 65% reduction in ALOX15 expression in healthy BECs at 24 hours (n = 6; P = 0.04) and a 42% reduction in gene expression in COPD BECs (n = 4; P = 0.11) (Figure 7B). H. influenzae infection resulted in a 2.2-fold increase in ALOX15 expression in COPD BECs at 24 hours (n = 5; P = 0.15) (Figure E10).

Figure 7.

Figure 7.

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Lipoxygenase-15 (ALOX15) gene expression is reduced in bronchial epithelial cells (BECs) from patients with chronic obstructive pulmonary disease (COPD) compared with healthy controls with rhinovirus (RV) infection decreasing ALOX15 expression. (A) ALOX15 and 18S were measured in cell lysates from COPD BECs (n = 8) and healthy BECs (n = 5). ALOX15 expression was corrected for 18S to produce relative gene expression. (B) COPD BECs (n = 4) and healthy BECs (n = 6) were infected with RV (multiplicity of infection = 1) for 6 and 24 hours. RV infection reduced expression of ALOX15 in healthy BECs at 24 hours. Friedman test, P = 0.048.

Discussion

In this analysis of the well-characterized London COPD Exacerbation Cohort, we observed a dynamic temporal change in sputum SPMs during bacteria-induced AECOPD and exacerbation recovery. In sharp contrast, viral exacerbations did not mobilize the same increase in airway SPMs and were associated with prolonged respiratory symptoms and delayed lung function recovery, compared with exacerbations where no virus was detected. The induction of sputum RvD1 in bacterial COPD exacerbation onset was significantly greater than in viral exacerbations, with lower levels of sputum RvD1 at 2 weeks being associated with delayed symptomatic recovery.

To our knowledge, this is the first longitudinal analysis of the temporal change in airway SPMs during COPD exacerbations. Here, the increased sputum RvD1 response with bacteria-induced AECOPD was distinguished from viral exacerbations and associated with a more rapid clinical recovery. We identified the decreased expression of ALOX15 in COPD BECs compared with healthy BECs, which could lead to a reduced SPM response to pathogens in COPD. In contrast to bacterial infection, in vitro RV infection of BECs reduced the expression of ALOX15, which could inhibit the synthesis of RvD1 during viral exacerbations. Alternatively, lipoxin A4 is an arachidonic acid–derived SPM that increases in plasma with AECOPD, but to a much lesser degree than the acute-phase reactant serum amyloid A, which interacts with the lipoxin receptor ALX/FPR2 to allosterically inhibit the SPM’s protective actions on BECs (32). Thus, AECOPD can induce local or systemic increases in SPMs, but this potentially protective response can be disrupted by altered production or receptor inhibition.

The impact of delayed exacerbation recovery and nonrecovery has not been well defined in COPD. In this study, median symptom duration was 14 days, which is similar to previous reports from our group and other outpatient cohorts (15, 17, 33), although a third had symptoms for 21 days or more. As previously described by Seemungal and colleagues, viral exacerbations were associated with delayed symptomatic recovery (16); however, lung function recovery was also delayed in viral exacerbations, compared with nonviral exacerbations, independent of the presence of bacteria in this study. There are several potential reasons for delayed recovery in viral exacerbations. First, there are no licensed antiviral treatments for COPD exacerbations, whereas antibiotics may be more effective at treating exacerbations driven by an outgrowth of bacteria (34); however, a dampened proresolution response may also contribute to prolonged airway inflammation in viral inflammation. It is also notable that a clinical trial of retreatment of unrecovered COPD exacerbations with ciprofloxacin or placebo at 2 weeks showed no difference in time to recovery in the ciprofloxacin group, suggesting that nonrecovery is not driven by bacterial infection (35).

Persistently elevated sputum proinflammatory cytokines IL-6 and CXCL8 during exacerbation recovery have previously been shown to be associated with delayed recovery (17, 33). Our finding that lower levels of RvD1 were associated with prolonged respiratory symptoms suggests a potential imbalance between proinflammatory and proresolving mediators in the airway, contributing to nonrecovery. We found positive relationships between proinflammatory cytokines CXCL10, IL-6, and CXCL8 at different time points during recovery, with a positive association between RvD1 and a marker of neutrophil activation, MPO, at 2 weeks. This may represent temporal changes in the recruitment of immune cells to the airway during exacerbations, as granulocytes such as neutrophils are required for the synthesis of RvD1. Alternatively, a higher airway inflammatory response may also lead to a greater counterregulatory SPM response. However, further work is needed to investigate the relationships between these mediators and airway immune cell response to pathogens in COPD.

In this study, targeted LC-MS/MS analysis of sputum identified that SPM RvD1 was induced in bacterial, but not viral, exacerbations of COPD. RvD1 reduced the IL-6 response to H. influenzae in vitro; H. influenzae also led to a nonsignificant increase in ALOX15 gene expression. Mouse models have shown that RvD1 and its 17-epimer can promote the resolution of sterile acute lung injury and bacterial pneumonia (30, 36), enhance bacterial clearance of H. influenzae (37) and S. pneumoniae (38), and attenuate the inflammatory cytokine response to cigarette smoke (38, 39), indicating lung-protective roles for RvD1 in these preclinical experimental models of COPD exacerbations.

Here, RvD1 decreased IL-6 expression after RV infection in BECs from patients with COPD, but RvD1 did not substantially impact IFN responses to viral infection in vitro, suggesting that RvD1 has the potential to modulate the inflammatory response through an IFN-independent pathway. RvD1 has previously been shown to modulate the inflammatory response to influenza infection by means of the Nrf pathway and polyionisinic polycytidylic acid through TAK1 in vitro (40, 41) suggesting that RvD1 may have broader activity in promoting the resolution of inflammation in both bacterial and viral infections. Recently, other DHA-derived SPMs (PD1 and MaR1) were shown to be protective for RSV infections in experimental model systems (28, 31). Unlike RvD1, PD1 and MaR1 were not significantly increased with bacterial-induced COPD exacerbations here, which suggests selective airway metabolic responses to RV and RSV for DHA-derived SPMs. Further in vivo studies are needed to understand the broader impact of respiratory viral infections on the DHA metabolome and whether RvD1 can promote resolution of inflammation after additional respiratory infections.

RvD1 is derived from DHA by sequential enzymatic conversion by ALOX15 in BECs and 5-lipoxygenase in granulocytes (42). In this study, we identified reduced expression of ALOX15 in BECs from patients with COPD compared with healthy controls, which could result in decreased synthesis of RvD1 in response to infection in COPD. Although there have been no other longitudinal studies of SPMs in COPD, Croasdell and colleagues identified lower levels of RvD1 in serum and BAL fluid from patients with COPD compared with healthy controls (43). Fisk and colleagues recently found lower levels of aggregate D-series resolvins and DHA metabolome in the serum of patients with COPD with frequent exacerbations compared with healthy controls, suggesting that there may be a defect in the synthesis of ALOX15-A5LOX–dependent SPMs in COPD (44). In addition, RvD1 ameliorates neutrophilic pulmonary inflammation and the development of emphysema in mouse models of cigarette smoke exposure (39, 45), suggesting that SPMs may have therapeutic potential to promote resolution of inflammation in COPD. However, further mechanistic studies including coinfection models are required to fully elucidate the effect of pathogens on the synthesis of SPMs in COPD.

It is also intriguing that, in population-based studies, higher levels of dietary DHA are associated with a slower decline in lung function (46), and a cross-sectional study of omega-3 fatty acid dietary intake was associated with fewer COPD exacerbations and a trend toward improved lung function (47). In addition, aspirin use, which may increase the synthesis of aspirin-triggered RvD1, has also been associated with reduced exacerbation frequency in some observational studies of COPD (48). Replication of these trials is needed to establish the potentially protective effects of dietary DHA supplementation or aspirin use on airway SPM production and actions to accelerate COPD exacerbation recovery.

The strengths of this study were the inclusion of a well-characterized group of patients with COPD who were trained in exacerbation reporting and diary carding of symptom recovery with the ability to integrate clinical recovery data and sputum lipid mediator profiling. There are several limitations, including a relatively small sample size, the absence of sputum cell use of bacterial culture methods rather than microbiome analysis. In addition, our in vitro work used BECs grown in submerged cell culture; as a result, these findings would need to be validated using an air–liquid interface model.

Conclusions

In summary, viral exacerbations of COPD were associated with delayed clinical recovery compared with nonviral exacerbations. There was a dynamic temporal change in select SPM levels in sputum during COPD exacerbations, with a greater induction of RvD1 in bacterial compared with viral exacerbations. Reduced levels of sputum RvD1 and RvE1 during exacerbation recovery were associated with prolonged respiratory symptoms, suggesting that treatment approaches targeting these proresolution pathways could enhance recovery from AECOPD.

Supplemental Materials

Supplementary data
rccm.202407-1325OCS1.docx (844.9KB, docx)
DOI: 10.1164/rccm.202407-1325OC

Acknowledgments

Acknowledgment

The authors thank all the participants who took part in this research study.

Footnotes

Supported by an NHLI Foundation Pilot Award scheme from the National Heart and Lung Institute, Imperial College London; by an NHLI Clinical Lectureship (to L.J.F.); by NHLBI grant R01HL122531 (to B.D.L.); and by an Academy of Medical Sciences Starter Grant for Clinical Lecturers (SGL026\1079 to L.J.F.). Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre.

Author Contributions: L.J.F., M.D., A.J.B., B.D.L., and J.A.W. conceived and designed the study. L.J.F., J.M., F.K., P.F., T.K., and F.B. performed experimental work. L.J.F., D.W., F.K., A.I.R., M.M., C.O., and S.K. collected clinical samples. L.J.F., J.M., D.W., F.K., P.B., and A.S. performed data analysis. L.J.F., S.L.J., P.B., J.P.A., A.J.M., A.S., A.J.B., J.A.W., and B.D.L. reviewed and drafted the manuscript.

A data supplement for this article is available via the Supplements tab at the top of the online article.

Artificial Intelligence Disclaimer: No artificial intelligence tools were used in writing this manuscript.

Originally Published in Press as DOI: 10.1164/rccm.202407-1325OC on March 5, 2025

Author disclosures are available with the text of this article at www.atsjournals.org.

References

  • 1. Diaz AA, Orejas JL, Grumley S, Nath HP, Wang W, Dolliver WR, et al. Airway-occluding mucus plugs and mortality in patients with chronic obstructive pulmonary disease. JAMA . 2023;329:1832–1839. doi: 10.1001/jama.2023.2065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax . 2005;60:925–931. doi: 10.1136/thx.2005.040527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Hartl S, Lopez-Campos JL, Pozo-Rodriguez F, Castro-Acosta A, Studnicka M, Kaiser B, et al. Risk of death and readmission of hospital-admitted COPD exacerbations: European COPD audit. Eur Respir J . 2016;47:113–121. doi: 10.1183/13993003.01391-2014. [DOI] [PubMed] [Google Scholar]
  • 4. Sivapalan P, Lapperre TS, Janner J, Laub RR, Moberg M, Bech CS, et al. Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): a multicentre, randomised, controlled, open-label, non-inferiority trial. Lancet Respir Med . 2019;7:699–709. doi: 10.1016/S2213-2600(19)30176-6. [DOI] [PubMed] [Google Scholar]
  • 5. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax . 2002;57:847–852. doi: 10.1136/thorax.57.10.847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Han MK, Quibrera PM, Carretta EE, Barr RG, Bleecker ER, Bowler RP, et al. SPIROMICS investigators Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. 2017;5:619–626. doi: 10.1016/S2213-2600(17)30207-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. George SN, Garcha DS, Mackay AJ, Patel AR, Singh R, Sapsford RJ, et al. Human rhinovirus infection during naturally occurring COPD exacerbations. Eur Respir J . 2014;44:87–96. doi: 10.1183/09031936.00223113. [DOI] [PubMed] [Google Scholar]
  • 8. Hutchinson AF, Ghimire AK, Thompson MA, Black JF, Brand CA, Lowe AJ, et al. A community-based, time-matched, case-control study of respiratory viruses and exacerbations of COPD. Respir Med . 2007;101:2472–2481. doi: 10.1016/j.rmed.2007.07.015. [DOI] [PubMed] [Google Scholar]
  • 9. Molyneaux PL, Mallia P, Cox MJ, Footitt J, Willis-Owen SA, Homola D, et al. Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med . 2013;188:1224–1231. doi: 10.1164/rccm.201302-0341OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Wang Z, Locantore N, Haldar K, Ramsheh MY, Beech AS, Ma W, et al. Inflammatory endotype-associated airway microbiome in chronic obstructive pulmonary disease clinical stability and exacerbations: a multicohort longitudinal analysis. Am J Respir Crit Care Med . 2021;203:1488–1502. doi: 10.1164/rccm.202009-3448OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Pfeffer PE, Donaldson GC, Mackay AJ, Wedzicha JA. Increased chronic obstructive pulmonary disease exacerbations of likely viral etiology follow elevated ambient nitrogen oxides. Am J Respir Crit Care Med . 2019;199:581–591. doi: 10.1164/rccm.201712-2506OC. [DOI] [PubMed] [Google Scholar]
  • 12. Liang L, Cai Y, Barratt B, Lyu B, Chan Q, Hansell AL, et al. Associations between daily air quality and hospitalisations for acute exacerbation of chronic obstructive pulmonary disease in Beijing, 2013–17: an ecological analysis. Lancet Planet Health . 2019;3:e270–e279. doi: 10.1016/S2542-5196(19)30085-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Hansel NN, McCormack MC, Kim V. The effects of air pollution and temperature on COPD. COPD . 2016;13:372–379. doi: 10.3109/15412555.2015.1089846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Dransfield MT, Kunisaki KM, Strand MJ, Anzueto A, Bhatt SP, Bowler RP, et al. COPDGene Investigators Acute exacerbations and lung function loss in smokers with and without chronic obstructive pulmonary disease. Am J Respir Crit Care Med . 2017;195:324–330. doi: 10.1164/rccm.201605-1014OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Donaldson GC, Law M, Kowlessar B, Singh R, Brill SE, Allinson JP, et al. Impact of prolonged exacerbation recovery in chronic obstructive pulmonary disease. Am J Respir Crit Care Med . 2015;192:943–950. doi: 10.1164/rccm.201412-2269OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Seemungal TAR, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med . 2000;161:1608–1613. doi: 10.1164/ajrccm.161.5.9908022. [DOI] [PubMed] [Google Scholar]
  • 17. Perera WR, Hurst JR, Wilkinson TMA, Sapsford RJ, Müllerova H, Donaldson GC, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J . 2007;29:527–534. doi: 10.1183/09031936.00092506. [DOI] [PubMed] [Google Scholar]
  • 18. Mallia P, Message SD, Gielen V, Contoli M, Gray K, Kebadze T, et al. Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am J Respir Crit Care Med . 2011;183:734–742. doi: 10.1164/rccm.201006-0833OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest . 2018;128:2657–2669. doi: 10.1172/JCI97943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Chiang N, Sakuma M, Rodriguez AR, Spur BW, Irimia D, Serhan CN. Resolvin T-series reduce neutrophil extracellular traps. Blood . 2022;139:1222–1233. doi: 10.1182/blood.2021013422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Dalli J, Serhan CN. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood . 2012;120:e60–e72. doi: 10.1182/blood-2012-04-423525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Duvall MG, Levy BD. DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation. Eur J Pharmacol . 2016;785:144–155. doi: 10.1016/j.ejphar.2015.11.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax . 2000;55:114–120. doi: 10.1136/thorax.55.2.114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Graham BL, Steenbruggen I, Barjaktarevic IZ, Cooper BG, Hall GL, Hallstrand TS, et al. Standardization of spirometry 2019 update: an official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med . 2019;200:e70–e88. doi: 10.1164/rccm.201908-1590ST. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. Development and first validation of the COPD Assessment Test. Eur Respir J . 2009;34:648–654. doi: 10.1183/09031936.00102509. [DOI] [PubMed] [Google Scholar]
  • 26. Singanayagam A, Glanville N, Girkin JL, Ching YM, Marcellini A, Porter JD, et al. Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations. Nat Commun . 2018;9:2229. doi: 10.1038/s41467-018-04574-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Kamal F, Kumar S, Edwards MR, Veselkov K, Belluomo I, Kebadze T, et al. Virus-induced volatile organic compounds are detectable in exhaled breath during pulmonary infection. Am J Respir Crit Care Med . 2021;204:1075–1085. doi: 10.1164/rccm.202103-0660OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Krishnamoorthy N, Walker KH, Brüggemann TR, Tavares LP, Smith EW, Nijmeh J, et al. The Maresin 1–LGR6 axis decreases respiratory syncytial virus-induced lung inflammation. Proc Natl Acad Sci USA . 2023;120:e2206480120. doi: 10.1073/pnas.2206480120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Tavares LP, Brüggemann TR, Rezende RM, Machado MG, Cagnina RE, Shay AE, et al. Cysteinyl maresins reprogram macrophages to protect mice from Streptococcus pneumoniae after influenza A virus infection. mBio . 2022;13:e0126722. doi: 10.1128/mbio.01267-22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Abdulnour RE, Sham HP, Douda DN, Colas RA, Dalli J, Bai Y, et al. Aspirin-triggered resolvin D1 is produced during self-resolving Gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation. Mucosal Immunol . 2016;9:1278–1287. doi: 10.1038/mi.2015.129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Walker KH, Krishnamoorthy N, Brüggemann TR, Shay AE, Serhan CN, Levy BD. Protectins PCTR1 and PD1 reduce viral load and lung inflammation during respiratory syncytial virus Infection in mice. Front Immunol . 2021;12:704427. doi: 10.3389/fimmu.2021.704427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Bozinovski S, Uddin M, Vlahos R, Thompson M, McQualter JL, Merritt AS, et al. Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease. Proc Natl Acad Sci USA . 2012;109:935–940. doi: 10.1073/pnas.1109382109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Mohan A, Prasad D, Sharma A, Arora S, Guleria R, Sharma SK, et al. Delayed resolution of inflammatory response compared with clinical recovery in patients with acute exacerbations of chronic obstructive pulmonary disease. Respirology . 2012;17:1080–1085. doi: 10.1111/j.1440-1843.2012.02216.x. [DOI] [PubMed] [Google Scholar]
  • 34. Mayhew D, Devos N, Lambert C, Brown JR, Clarke SC, Kim VL, et al. AERIS Study Group Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations. Thorax . 2018;73:422–430. doi: 10.1136/thoraxjnl-2017-210408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Ritchie AI, Brill SE, Vlies BH, Finney LJ, Allinson JP, Alves-Moreira L, et al. Targeted retreatment of incompletely recovered chronic obstructive pulmonary disease exacerbations with ciprofloxacin. A double-blind, randomized, placebo-controlled, multicenter, phase III clinical trial. Am J Respir Crit Care Med . 2020;202:549–557. doi: 10.1164/rccm.201910-2058OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Eickmeier O, Seki H, Haworth O, Hilberath JN, Gao F, Uddin M, et al. Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. Mucosal Immunol . 2013;6:356–266. doi: 10.1038/mi.2012.66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Croasdell A, Lacy SH, Thatcher TH, Sime PJ, Phipps RP. Resolvin D1 dampens pulmonary inflammation and promotes clearance of nontypeable Haemophilus influenzae. J Immunol. 2016;196:2742–2752. doi: 10.4049/jimmunol.1502331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Bhat TA, Kalathil SG, Bogner PN, Lehmann PV, Thatcher TH, Sime PJ, et al. AT-RvD1 mitigates SHS-exacerbated pulmonary inflammation and restores SHS-suppressed anti-bacterial immunity. J Immunol . 2021;206:1348. doi: 10.4049/jimmunol.2001228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Hsiao HM, Sapinoro RE, Thatcher TH, Croasdell A, Levy EP, Fulton RA, et al. A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation. PLoS One . 2013;8:e58258. doi: 10.1371/journal.pone.0058258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Guo Y, Tu YH, Wu X, Ji S, Shen JL, Wu HM, et al. ResolvinD1 protects the airway barrier against injury induced by influenza A virus through the Nrf2 pathway. Front Cell Infect Microbiol . 2020;10:616475. doi: 10.3389/fcimb.2020.616475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Hsiao HM, Thatcher TH, Levy EP, Fulton RA, Owens KM, Phipps RP, et al. Resolvin D1 attenuates polyinosinic-polycytidylic acid–induced inflammatory signaling in human airway epithelial cells via TAK1. J Immunol . 2014;193:4980–4987. doi: 10.4049/jimmunol.1400313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med . 2000;192:1197–1204. doi: 10.1084/jem.192.8.1197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Croasdell A, Thatcher TH, Kottmann RM, Colas RA, Dalli J, Serhan CN, et al. Resolvins attenuate inflammation and promote resolution in cigarette smoke–exposed human macrophages. Am J Physiol Lung Cell Mol Physiol . 2015;309:L888–L901. doi: 10.1152/ajplung.00125.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Fisk M, Gomez EA, Sun Y, Mickute M, McEniery C, Cockcroft JR, et al. Dysregulation of lipid mediators in patients with frequent exacerbations of chronic obstructive pulmonary disease. ERJ Open Res . 2025:00950–2023. doi: 10.1183/23120541.00950-2023. https://publications.ersnet.org/content/erjor/early/2024/08/22/23120541.00950-2023 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Posso SV, Quesnot N, Moraes JA, Brito-Gitirana L, Kennedy-Feitosa E, Barroso MV, et al. AT-RVD1 repairs mouse lung after cigarette smoke-induced emphysema via downregulation of oxidative stress by NRF2/KEAP1 pathway. Int Immunopharmacol . 2018;56:330–338. doi: 10.1016/j.intimp.2018.01.045. [DOI] [PubMed] [Google Scholar]
  • 46. Patchen BK, Balte P, Bartz TM, Barr RG, Fornage M, Graff M, et al. Investigating associations of omega-3 fatty acids, lung function decline, and airway obstruction. Am J Respir Crit Care Med . 2023;208:846–857. doi: 10.1164/rccm.202301-0074OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Lemoine C, Brigham E, Woo H, Koch A, Hanson C, Romero K, et al. Relationship between omega-3 and omega-6 fatty acid intake and chronic obstructive pulmonary disease morbidity. Ann Am Thorac Soc . 2020;17:378–381. doi: 10.1513/AnnalsATS.201910-740RL. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Fawzy A, Putcha N, Aaron CP, Bowler RP, Comellas AP, Cooper CB, et al. SPIROMICS Investigators Aspirin use and respiratory morbidity in COPD: a propensity score-matched analysis in Subpopulations and Intermediate Outcome Measures in COPD Study. Chest . 2018;155:519–527. doi: 10.1016/j.chest.2018.11.028. [DOI] [PMC free article] [PubMed] [Google Scholar]

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DOI: 10.1164/rccm.202407-1325OC

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