COPD 통시적 탐구!!

[문형철]

이 문서는

NHLBI/WHO 주도의 GOLD(Global Initiative for Chronic Obstructive Lung Disease) 워크숍 보고서의 핵심 내용으로,

만성폐쇄성폐질환(COPD)의 진단·관리·예방에 대한 최초의 국제적 합의 지침입니다. 

1. 정의 (Definition)

• COPD는 기류 제한(airflow limitation)이 특징인 질환으로, 완전히 가역적이지 않고 진행성이며, 폐의 유해 입자/가스에 대한 비정상적 염증 반응과 관련됩니다.
• 주요 증상: 만성 기침, 가래, 호흡곤란(dyspnea).
• 진단 확인: 폐활량계(spirometry) — 기관지확장제 투여 후 FEV1/FVC < 70% + FEV1 < 80% predicted (post-bronchodilator).

2. 중증도 분류 (Classification of Severity)

• GOLD 0 (At Risk): 위험 요인 노출 + 증상 있음 (FEV1 정상).
• GOLD 1 (Mild): FEV1 ≥ 80% predicted.
• GOLD 2 (Moderate): FEV1 50–79%.
• GOLD 3 (Severe): FEV1 30–49%.
• GOLD 4 (Very Severe): FEV1 < 30% (또는 호흡부전).

3. 병인 및 병태생리 (Pathogenesis, Pathology, Pathophysiology)

• 주요 위험요인: 흡연 (가장 중요), 직업성 노출, 실내/외 대기오염.
• 병리: 기도 염증, 점액 과다 분비, 폐기종(emphysema)으로 인한 탄성 저하.
• 결과: 기류 제한, 공기 trapping, V/Q mismatch → 호흡곤란, 만성 저산소/고이산화탄소혈증.

4. COPD 관리의 4가지 구성 요소 (Four Components of Management)

이 보고서의 핵심 프레임워크입니다.

1. 질환 평가 및 모니터링 (Assess and Monitor Disease)
   • 증상, 폐기능, 위험요인 평가.
   • 지속적 모니터링: 증상 악화, 합병증, 삶의 질.
2. 위험요인 감소 (Reduce Risk Factors)
   • 금연이 가장 중요 (예방 및 진행 억제에 최고 효과).
   • 직업/환경 노출 최소화.
3. 안정기 COPD 관리 (Manage Stable COPD)
   • 교육: 자기관리, 질환 이해.
   • 약물 치료:
     • 기관지확장제 (Bronchodilators): β2-agonist (short/long-acting), anticholinergics — 증상 완화의 주축.
     • 흡입 스테로이드 (ICS): 중증/빈번한 악화 환자에 선택적 사용 (Evidence B/C).
     • 기타: 백신(인플루엔자, 폐렴구균), mucolytics 등.
   • 비약물 치료: 폐재활(pulmonary rehabilitation), 장기 산소 요법(LTOT — PaO2 ≤55 mmHg 등 기준), 수술(폐용적축소술, 이식 등).
4. 급성 악화 관리 (Manage Exacerbations)
   • 원인 평가 (감염, 환경 등).
   • 가정/병원 관리: 기관지확장제, 전신 스테로이드 (단기), 항생제 (적응증 시), 비침습적 환기(NIPPV).
   • 퇴원 후 추적: 4–6주 내 재평가.

주요 강조점

• COPD는 예방 가능하고 치료 가능한 질환이지만, 조기 진단과 지속적 관리가 핵심.
• 흡연 중단이 가장 효과적인 단일 개입.
• 다학제적 접근: 약물 + 비약물 + 교육 + 위험요인 제거.
• 전 세계적 인식 제고와 연구 촉진 (GOLD Initiative의 목적).

다국가(25개국), 무작위배정, 이중맹검, 평행군, 위약 대조

1년 추적 RCT

연구 배경 및 목적

• COPD에서 장기작용 β2 작용제 (Salmeterol, LABA)와 흡입 코르티코스테로이드 (Fluticasone, ICS) 단독 요법의 효과는 알려져 있었으나, 병용 요법의 우수성을 확인하고자 함.
• 가설: LABA + ICS 병용이 각 단독 요법보다 폐기능, 증상, 삶의 질, 악화 빈도에서 더 우수할 것이다.

연구 방법

• 대상: COPD 환자 1,465명 (외래, FEV1 25~70% predicted, FEV1/FVC <70%, 흡연력 ≥10 pack-year 등).
• 중재 (2회/일):
  • Salmeterol 50 μg (n=372)
  • Fluticasone 500 μg (n=374)
  • Salmeterol 50 μg + Fluticasone 500 μg 병용 (n=358)
  • Placebo (n=361)
• 1차 결과: 12개월 pre-bronchodilator FEV1 변화.
• 2차 결과: 증상, 삶의 질 (SGRQ), 악화 빈도, 구제약 사용, 안전성 (부작용, 코르티솔, 피부 멍 등).

주요 결과

1. 폐기능 (FEV1):
   • 병용군이 가장 우수 (placebo 대비 +133 mL, salmeterol 대비 +73 mL, fluticasone 대비 +95 mL, 모두 p<0.0001).
   • 효과는 2주부터 나타나 1년 내내 지속.
2. 증상 및 삶의 질:
   • 병용군에서 일상 증상 감소가 가장 크고, SGRQ 점수 개선이 임상적으로 의미 있는 수준 (다른 군보다 우수).
   • 구제약(단기 β2 작용제) 사용도 가장 적음.
3. 악화 (Exacerbations):
   • 모든 활성 치료군에서 위약 대비 19~25% 감소 (병용군이 수치상 가장 좋았으나, 단독군 간 유의미 차이는 제한적).
4. 안전성:
   • 모든 군에서 잘 견딤. 구강 칸디다증은 ICS 함유군(단독/병용)에서 약간 증가했으나, 전신 부작용(코르티솔 저하, 멍, 심전도 이상)은 유의미 차이 없음.

해석 및 결론 (Interpretation)

• LABA + ICS 병용 요법은 COPD 환자에서 폐기능 개선, 증상 조절, 삶의 질 향상 측면에서 단독 요법보다 우수하며, 추가적인 안전성 문제는 없었다.
• 따라서 중증 COPD 환자(특히 빈번한 악화 또는 증상이 심한 경우)에서 이 조합을 고려해야 한다고 제안.

1. 2013 GOLD (두 번째 5년 개정판)

• 주요 특징: 2001년 이후 축적된 지식을 종합한 대대적 업데이트. Spirometry를 진단의 필수 조건으로 명확히 하고, ABCD 그룹 분류를 도입한 버전입니다.
• 환자 평가의 4가지 요소:
  1. 증상 (Symptoms: mMRC or CAT)
  2. 기류 제한 정도 (Spirometry: GOLD 1~4)
  3. 미래 악화 위험 (Exacerbation history)
  4. 동반질환 (Comorbidities) — 새롭게 강조
• ABCD 그룹 (증상 + 악화 위험 기준):
  • A: 증상 적음 + 악화 위험 낮음
  • B: 증상 많음 + 악화 위험 낮음
  • C: 증상 적음 + 악화 위험 높음
  • D: 증상 많음 + 악화 위험 높음
• 치료: 그룹별 비약물/약물 치료 매칭 (LABA/LAMA 중심, ICS는 C/D에서 선택적).
• 새로운 섹션: 악화(Exacerbations) 관리 상세화, 동반질환 관리.

의의: COPD를 다차원 질환으로 보고, 증상·위험 중심의 개인화 치료를 강화. Spirometry 진단 필수화로 과진단 방지.

2. 2017 GOLD Executive Summary

• 주요 변화 (2013 대비 가장 큰 개정):
  1. 평가 분리: Spirometry (기류 제한 정도)는 진단/중증도에만 사용. ABCD 그룹은 증상 + 악화 이력만으로 결정 (폐기능과 분리).
  2. 치료 에스컬레이션/디에스컬레이션: 각 그룹별 초기 치료 + 추적 시 조정 전략 명확화.
  3. 비약물 치료 포괄적 제시 (폐재활, 백신, 영양, 운동 등).
  4. 동반질환 관리 강조 — COPD 치료 시 반드시 고려.
  5. 악화 예방 및 탈-스테로이드 전략 도입.
• 약물 치료 트렌드:
  • LAMA/LABA 듀얼 요법 강화.
  • ICS는 eosinophil 높거나 악화 빈번 환자에 우선.
  • De-escalation (치료 축소) 개념 신규 도입.

의의: 환자 중심·증거 기반 접근을 더 정교하게 다듬음. 이후 GOLD 지침의 현대적 틀을 마련.

2001 → 2007 → 2013 → 2017 비교 (간단)연도핵심 혁신

2001	4가지 관리 구성 요소 기본 틀
2007	LABA/ICS 병용 근거 강화, comorbidity 언급
2013	ABCD 그룹 도입, Spirometry 필수
2017	ABCD를 증상+악화 중심으로 재정의, escalation/de-escalation

1. FLAME 연구 (2016) — Indacaterol/Glycopyrronium (LABA/LAMA) vs Salmeterol/Fluticasone (LABA/ICS)

• 저자: Wedzicha et al.
• 디자인: 무작위, 이중맹검, 52주, 중증~매우중증 COPD (악화 이력 있음).
• 주요 결과:
  • 1차 endpoints: LABA/LAMA 듀얼 요법이 LABA/ICS보다 급성 악화 발생률 유의미 감소 (rate ratio 0.83).
  • 폐기능(FEV1), 증상, 삶의 질에서도 LABA/LAMA 우위 또는 동등.
  • 특히 pneumonia 발생률: LABA/ICS군에서 더 높음.
• 의의: ICS 불필요한 환자에서 LABA/LAMA 듀얼이 표준 1차 치료로 자리매김. Eosinophil 낮은 환자에서 ICS 피할 근거 제공.

2. IMPACT 연구 (2018) — Single-Inhaler Triple (LABA/LAMA/ICS) vs Dual Therapy

• 저자: Lipson et al. (IMPACT Investigators)
• 디자인: 대규모 (10,000명+), 52주, 이전에 악화 경험이 있는 COPD 환자.
• 주요 결과:
  • Triple therapy (fluticasone furoate/umeclidinium/vilanterol)가 LABA/LAMA 또는 LABA/ICS 듀얼보다 급성 악화율 유의미 감소.
  • FEV1 개선, 삶의 질 향상, 입원 감소.
  • Pneumonia 위험: ICS 포함군에서 증가 (Triple > Dual).
• 의의: 악화 빈번 + eosinophil 높은 환자에서 Triple therapy의 우수성 입증. Single inhaler 편의성 강조.

3. ETHOS 연구 (2020) — Triple Therapy의 두 가지 ICS 용량 비교

• 저자: Rabe et al. (ETHOS Investigators)
• 디자인: budesonide/glycopyrrolate/formoterol Triple therapy (고용량 ICS vs 저용량 ICS) vs Dual (LABA/LAMA).
• 주요 결과:
  • 두 Triple 군 모두 Dual보다 악화율 유의미 감소 (고용량이 약간 더 우수).
  • 폐기능·증상 개선.
  • ICS 용량: 저용량도 상당한 효과 + pneumonia 위험 상대적으로 낮음.
• 의의: Triple therapy 용량 최적화 근거. 고위험 환자에서 Triple이 표준이 됨.

4. BOREAS 연구 (2023) — Dupilumab (Dupixent, anti-IL4/13) for Type 2 COPD

• 저자: Bhatt et al. (BOREAS Investigators)
• 디자인: eosinophil ≥300/μL, Type 2 inflammation (혈액 eosinophil 높음) COPD 환자, 52주.
• 주요 결과:
  • Dupilumab + 표준 치료가 급성 악화율 유의미 감소 (약 30% 감소).
  • FEV1 개선, 증상·삶의 질 향상.
  • 안전성 양호 (알레르기/기생충 관련 주의).
• 의의: Eosinophilic (Type 2) COPD에서 생물학적 제제의 첫 번째 강력 근거. 기존 ICS 중심에서 벗어나 정밀의학 시대 개막.

이 논문은 COPD의 임상적 측면(진단, 평가, 치료, 합병증, 예후)을 체계적으로 업데이트한 리뷰입니다. GOLD 지침과 연계하여 실무 중심으로 설명하며, 동반질환·다기관 영향도 강조합니다.

1. 서론 및 역학

• COPD는 전 세계 3대 사망 원인 (2017년 320만 명 사망, 2040년 440만 명 예상).
• 여성에서 유병률·사망률 증가 추세 (특히 개발도상국).
• 흡연 외에 바이오매스 연료, 대기오염, 조기 폐 손상 등이 중요 위험요인.
• COPD는 전신 질환 — 폐 외에 심혈관, 근육, 골격, 정신건강 등 다기관 영향.

2. 진단 (Diagnosis)

• 의심: 40세 이상, 호흡곤란·기침·가래 + 위험요인(흡연 등) → Spirometry 필수.
• 확진: Post-bronchodilator FEV1/FVC < 0.70.
• 중증도: GOLD 1~4 (FEV1 % predicted).
• 추가 평가: 증상 (mMRC, CAT), 악화 이력, 동반질환, CT (emphysema/small airway disease), 운동능력(6MWT) 등 다차원 평가 권고.

3. 병태생리 및 표현형 (Phenotypes)

• 주요 기전: 만성 염증, 기도 재형성, 폐기종, small airway disease.
• 표현형:
  • Emphysema-dominant vs Airway-dominant.
  • Frequent exacerbator.
  • Asthma-COPD overlap (ACO).
  • Eosinophilic inflammation (ICS 반응 좋음).
• 동반질환 (Comorbidities): 심부전, 관상동맥질환, 골다공증, 우울증, 폐암 등 — COPD 사망의 주요 원인.

4. 치료 (Management)

• 비약물 치료 (항상 우선):
  • 금연 — 가장 효과적.
  • 폐재활 (Pulmonary Rehabilitation) — 증상·운동능력·삶의 질 크게 개선.
  • 백신 (인플루엔자, 폐렴구균).
  • 영양, 운동, 자기관리 교육.
• 약물 치료 (GOLD ABCD 기반, 2019 시점):
  • 초기: LAMA (Long-acting muscarinic antagonist) 단독 또는 LABA/LAMA 듀얼.
  • 증상 지속/악화: LABA/LAMA + ICS (Triple therapy) 고려.
  • 악화 예방: LABA/LAMA 듀얼이 LABA/ICS보다 우수 (FLAME 연구 등).
  • 구제약: SABA/SAMA.
  • 기타: Roflumilast (만성 기관지염·중증 악화), Azithromycin (선택적).
• 급성 악화 관리:
  • Bronchodilator, 전신 스테로이드 (5~7일), 항생제 (적응증 시).
  • NIV (비침습적 환기) — 호흡부전 시 생존율 향상.
  • 입원 후 조기 재활·추적 중요.
• 고급 치료:
  • 장기 산소 요법 (LTOT) — 휴식 시 PaO2 ≤55 mmHg 등.
  • 폐용적축소술, 이식 (선택적).
  • Alpha-1 antitrypsin 보충 (유전형).

5. 예후 및 모니터링

• 예후 인자: FEV1, 악화 빈도, 동반질환, 영양 상태, 운동능력 (BODE index 등).
• 악화는 COPD 진행의 주요 driver — 악화 1회 후 폐기능 저하 가속.
• 정기 평가: 증상, 폐기능, 악화, 동반질환, inhaler technique.

6. 임상적 함의 (Celli & Wedzicha 관점)

• COPD는 예방·조기 개입 가능한 질환.
• 개인화 치료 (phenotype, biomarker — eosinophil 등) 중요.
• 통합 케어 (Integrated Care): 폐 전문의 + 다학제 팀.
• 미래 방향: Precision Medicine, biologics, 디지털 헬스.

연구 배경

COPD(만성폐쇄성폐질환)와 크론병(Crohn’s disease, CD)은

공통 염증·면역 기전을 공유하는 동반질환(Comorbidity)으로 알려져 있습니다.

이 연구는

bioinformatics(생물정보학) 기법을 활용해

두 질환의 공통 분자 기전을 탐색했습니다.

주요 방법

• 데이터: GEO(Gene Expression‎ Omnibus) microarray 데이터셋 분석.
• 분석:
  • 공통 차별발현유전자 (coDEGs): 349개 식별.
  • Hub gene (핵심 유전자): 8개 (CCL2, CXCL1, TLR2, ICAM1, PTPRC, ITGAX, PTGS2, MMP9).
  • Immune cell infiltration: ssGSEA(single-sample gene set enrichment analysis)로 분석.
  • 잠재 약물: Connectivity Map (CMAP)으로 예측.

주요 결과

1. 공통 Hub Gene 8개:
   • 염증·면역 조절 핵심: CCL2, CXCL1 (chemokine), TLR2 (Toll-like receptor), ICAM1 (adhesion molecule), MMP9 (matrix metalloproteinase) 등.
   • 이 유전자들은 면역 기능과 염증 반응 조절에 핵심적이며, 두 질환의 공통 병태생리를 설명.
2. 면역세포 침윤:
   • COPD와 CD에서 공통 면역세포 활성화 패턴 확인 (예: macrophage, neutrophil 등 증가).
3. 잠재 치료제:
   • CMAP 분석으로 coDEGs 관련 후보 약물 제안 (구체적 약물명은 논문에서 확인).

결론 및 의의

• COPD와 크론병은 공유된 염증·면역 네트워크 (특히 chemokine, TLR, MMP 경로)를 통해 상호 영향을 줌.
• 새로운 관점: 두 질환의 공통 치료 타겟 (hub gene) 발굴 → 통합 치료 전략 가능성 제시.
• 한계: Bioinformatics 기반 (실험 검증 필요), 데이터셋 제한.

https://pmc.ncbi.nlm.nih.gov/articles/PMC13109179/

이 논문은

GOLD 2026 보고서의 주요 변경점과 임상적 의미를

체계적으로 분석한 리뷰입니다.

2025년 보고서와 비교하며,

조기 개입(Early Intervention),

다차원 평가(Multi-dimensional Assessment),

개인화 치료(Personalized Care)를 핵심 테마로 강조합니다.

1. 전체적인 변화 방향 (Abstract & Key Points)

• 기존 틀 유지: Spirometry 정의 (post-BD FEV1/FVC <0.70)는 그대로.
• 새로운 패러다임:
  • Disease Activity (질환 활동성): 증상 조절을 넘어 생물학적 활동성을 치료 목표로 설정. 조기 개입으로 진행 억제.
  • ABE 분류 개선: Group E(고위험) 기준 완화 → 1년 내 1회 중등도 이상 악화만으로도 E군.
  • 혈중 호산구(Eosinophil): ICS 사용 지표로 강화 (≥300/μL에서 강력 추천).
  • 비약물 치료를 핵심 질환 조절 전략으로 승격 (폐재활, 금연, 백신, 자기관리, 악화 후 케어).
  • 생물학적 제제: Dupilumab, Mepolizumab — 호산구 증가형(Eosinophilic) COPD 악화 환자에서 추가 옵션.
  • AI/디지털 기술: 새로운 장(chapter) 신설 — 진단, 위험 예측, 스마트 인haler, 원격 모니터링 등.

2. 진단 및 평가 (Diagnosis & Assessment)

• 조기 발견 강조: 무증상 저위험군 대규모 스크리닝은 비추천. 고위험군 대상 케이스 파인딩(증상+위험요인) 적극 권고.
• 다차원 평가 5가지 영역:
  1. FEV1 % predicted
  2. 증상 부담 (mMRC, CAAT/CAT, SGRQ)
  3. 악화 이력
  4. 혈중 호산구
  5. 동반질환 (Comorbidities — 심혈관, 대사, 정신건강 등)
• 'At Risk' 개념 강화: 증상 있으나 spirometry 정상인 경우도 지속 관찰.

3. 치료 전략 (Management)

• 초기 치료: Dual Bronchodilation (LABA + LAMA)을 대부분 1차 선택.
• Escalation (강화): Dual에도 불구하고 증상 지속/악화 시 Biomarker-guided Triple Therapy (ICS 추가).
• De-escalation (축소): ICS 불필요 시 점차 줄이기.
• 비약물 치료:
  • 폐재활, 금연, 백신, 산소/NIV, 악화 후 번들 케어 → 질환 수정(Disease-modifying) 전략으로 격상.
• 생물학적 제제: Dupilumab (anti-IL4/13), Mepolizumab (anti-IL5) — Type 2 염증(호산구 증가) 환자에서 악화 예방 효과 인정. 다만 비용-효과성, 일반화 한계 지적.

4. 급성 악화 관리 (Exacerbations)

• Rome 제안 기반 생리학적 중증도 분류 도입.
• 조기 개입, 퇴원 번들, 신속 추적 관찰 강조.

5. AI 및 신기술

• AI-assisted 진단, 위험 예측, 스마트 인haler, 텔레헬스 등 — 미래 지향적이나, 증거 부족과 편향 문제 지적.

6. 한계와 전망 (Critique)

• 강점: 정밀의학(Precision Medicine) 강화, 조기 개입, 개인화.
• 한계: 바이오마커 변동성, 신약 비용/접근성, 실증 부족.
• 임상 적용: 맥락에 맞는 신중한 적용 필요. 지속적인 검증 필수.

https://publications.ersnet.org/content/errev/30/160/200364?implicit-login=true%26324

이 논문은

COPD(만성폐쇄성폐질환)의 기존 질병 모델을 재평가하고,

더 통합된 새로운 작업 모델(working disease model)을 제안하는 리뷰 논문입니다.

GOLD 가이드라인 중심의 전통적 관점을 존중하면서도,

최근 병태생리학적 연구 결과를 종합해 치료 전략을 넓히려는 목적입니다.

핵심 메시지 (Abstract 중심)

기존 COPD 모델은

기도 벽의 “만성 염증”을 과도하게 강조한다고 비판합니다.

좌측: 정상 비흡연자 (Never smokers)

• 총 세포 수: mm²당 3,900개
• Stromal cells (기질 세포): 71% (n=2,769) ← 가장 큰 부분 (파란색)
• Macrophages (대식세포): 13% (n=507)
• Neutrophils (호중구): 4% (n=156)
• CD8 T-cells: 4% (n=156)
• Mast cells (비만세포): 5% (n=195)
• Fibroblasts (섬유아세포): 2% (n=78)
• Myofibroblasts (근섬유아세포): 1% (n=51)

→ 정상 소기도는 기질 세포(Stromal cells)가 압도적으로 많고, 전체적으로 세포 밀도가 높음.

---

우측: 현재 흡연 COPD 환자 (COPD-CS)

• 총 세포 수: mm²당 2,800개 (약 28% 감소)
• Myofibroblasts (근섬유아세포): 36% (n=1,000) ← 가장 큰 부분 (녹색)
• Stromal cells (기질 세포): 25% (n=708)
• Macrophages: 18% (n=504)
• CD8 T-cells: 9% (n=252)
• Neutrophils: 5% (n=140)
• Mast cells: 4% (n=112)
• Fibroblasts: 3% (n=84)

---

이 그림이 보여주는 핵심 메시지 (논문 맥락)

• COPD 소기도는 전체 세포 수가 크게 감소(hypocellularity)되어 있습니다. (정상 3,900 → COPD 2,800)
• Stromal cells 비율이 급격히 줄고, 대신 Myofibroblasts (근섬유아세포)가 크게 증가 → 섬유화(fibrosis)와 remodelling(재형성)이 진행되고 있음을 시사.
• 염증 세포(호중구, 대식세포 등)의 절대 수 증가도 미미하며, 대부분 흡연 자체로 인한 변화.
• 이는 “기도 벽에 만성 염증이 주된 병리”라는 기존 가설을 반박하고, 재형성(특히 EMT 관련 myofibroblast 증가)이 핵심임을 뒷받침하는 중요한 증거입니다

대신:

• 병변은 patchy(국소적)하고 variable(다양)하며, 핵심은 airway remodelling(기도 재형성)이다.
• 기도 벽 병리는 hypocellular(세포 감소), hypovascular(혈관 감소), destructive(파괴적), fibrotic(섬유화) 성격이 강함.
• Epithelial-Mesenchymal Transition (EMT) 스펙트럼이 재형성의 주요 동인.
• 산화 스트레스(oxidative stress), 기도 내 세균 colonization/infection(특히 respiratory bacteria), 폐암 발생 기전 등과 통합.

결론적으로, 무증상 흡연자와 초기 COPD(pre-COPD)에 초점을 맞춘 예방·치료 접근이 필요하다고 제안합니다.

주요 논점 상세

1. 기존 “염증 중심” 모델 비판
   • GOLD 모델: 흡연 → 비정상적 염증 → 조직 손상 → COPD (악순환).
   • 문제: 기도 벽에서의 염증 증거가 약함. 오히려 luminal(기도 내강) 염증이 주를 이룸.
   • 연구 예: COPD 기도 벽은 전체 세포 수가 감소(hypocellularity)하며, CD8+ 림프구 증가 외에 뚜렷한 염증 세포 증가가 적음.
2. Airway Remodelling 중심 모델 제안
   • Small airway(<2mm) thickening, narrowing, obliteration(소실)이 COPD의 핵심 병리.
   • Micro-CT 연구: 초기 COPD에서도 small airway 40% 이상 소실.
   • EMT(상피-간엽 전이): 상피 세포가 섬유아세포-like 세포로 바뀌며 섬유화·재형성 유발. 흡연이 EMT를 촉진.
3. 통합 요소
   • 산화 스트레스 → 상피 손상 → EMT.
   • 기도 내 세균 지속 colonization → luminal inflammation.
   • 폐암과의 연계 (공통 병리 기전).
   • Patchy nature: 병변이 균일하지 않고 일부 기도에 집중.
4. 임상적 함의 (Therapeutic Vision 확대)
   • GOLD 중심의 증상·악화 관리에서 벗어나 조기 개입 강조 (asymptomatic smoker, pre-COPD).
   • 기존 항염증제 한계 극복: 항섬유화, EMT 조절, 산화 스트레스 완화 치료 개발 필요.
   • IPF(특발성폐섬유증) 치료제( nintedanib, pirfenidone)나 종양 분야 EMT 표적 약물의 COPD 적용 가능성 언급.

왼쪽 상단 → 오른쪽으로 진행되는 병리 과정

1. 유발 요인 (Trigger)
   • 담배 연기 (Cigarette smoke)
   • Toxic luminal environment (독성 내강 환경)
   • ↑ Airway infections (기도 감염 증가)
   • ↑ Luminal inflammation (내강 염증 증가)
2. 중심 기전: ROS 및 상피 활성화
   • ROS oxidants (활성산소종, 산화 스트레스) ↑
   • Epithelial activation (상피 세포 활성화): TGF-β 및 다른 성장인자
3. EMT 과정 (좌측 빨간 박스)
   • Basal cells (기저 세포)에서 EMT activation
   • Cytoplasmic signalling: Kinase activation, TF activation, ↑ SMADs, STATs, β-catenin
   • Nuclear signalling: ↑ Twist, Snail, Slug, ZEB (전사인자)
   • → Epithelial/mesenchymal transitioning cell (상피-간엽 전이 중인 세포)
4. 결과 (아래쪽)
   • Myofibroblast proliferation (근섬유아세포 증식) ↑
   • RBM thickening and fragmentation (기저막 thickening 및 파편화)
   • Increased and altered ECM proteins (세포외기질 단백질 증가 및 변화): Fibronectin, Vitronectin, Collagen fibre
   • Airway thickening (기도 벽 비후) ↑
   • Airflow obstruction (기류 폐쇄) ↑

---

이 그림이 전달하는 핵심 메시지

• COPD의 핵심 병리는 단순한 염증이 아니라, 흡연 → 산화 스트레스 → EMT → 기도 재형성(airway remodelling)이라는 연속 과정입니다.
• EMT는 상피 세포가 간엽 세포(섬유아세포/근섬유아세포) 특징을 획득하는 과정으로, 기도 벽을 두껍게 하고 섬유화시켜 영구적인 기류 폐쇄를 초래합니다.
• TGF-β가 핵심 매개체이며, ROS(산화 스트레스)가 강력한 촉진제입니다.
• 기도 내강의 감염·염증은 EMT를 더욱 악화시키는 악순환을 만듭니다.

그림 구조 번역 및 설명 좌측 상단: Secondary phenomena (2차 현상) 우측 상단: Primary phenomena (1차 현상)
중심 원인

• Cigarette smoke (CS) (담배 연기) ← 모든 것의 시작

1차 현상 (Primary phenomena)

• Airway lumen (기도 내강)
  • Infections (감염)
  • CS-generated ROS (담배연기 유발 활성산소)
  • ↑ Macrophages (대식세포), ↑ Neutrophils (호중구)
• Airway wall (기도 벽)
  • ↑ Small airway fibrosis and destruction (소기도 섬유화 및 파괴)
  • ↑ Squamous metaplasia (편평상피화생)
  • ↑ Mucus hypersecretion (점액 과다 분비)
• Basal cell “reprogramming” (기저세포 재프로그래밍)
• EMT (상피-간엽 전이) ← 핵심 연결 고리

결과 (우측)

• COPD (직접적 결과)
• ↑ Daily symptoms (일상 증상)
• ↑ AECOPD (급성 악화)
• ↓ QoL (삶의 질 저하)
• ↑ Economic burden (경제적 부담)

다른 주요 결과 (좌측)

• Emphysema (폐기종) + ↑ Chronic airflow obstruction (만성 기류 폐쇄)
• Lung cancer (Death!) (폐암 — 사망!)

Review  Open access

Fully integrating pathophysiological insights in COPD: an updated working disease model to broaden therapeutic vision

• E. Haydn Walters
• Shakti D. Shukla 
• Malik Q. Mahmood

Show More

European Respiratory Review 2021 30(160): 200364; DOI: https://doi.org/10.1183/16000617.0364-2020

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This article appears in:

European Respiratory Review

Vol 30 Issue 160

 Focus PreviousNext

• Article
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Abstract

Our starting point is that relatively new findings into the pathogenesis and pathophysiology of airway disease in smokers that lead to chronic obstructive pulmonary disease (COPD) need to be reassessed as a whole and integrated into “mainstream” thinking along with traditional concepts which have stood the test of time. Such a refining of the accepted disease paradigm is urgently needed as thinking on therapeutic targets is currently under active reconsideration. We feel that generalised airway wall “inflammation” is unduly over-emphasised, and highlight the patchy and variable nature of the pathology (with the core being airway remodelling). In addition, we present evidence for airway wall disease in smokers/COPD as including a hypocellular, hypovascular, destructive, fibrotic pathology, with a likely spectrum of epithelial–mesenchymal transition states as significant drivers of this remodelling. Furthermore, we present data from a number of research modalities and integrate this with the aetiology of lung cancer, the role of chronic airway luminal colonisation/infection by a specific group of “respiratory” bacteria in smokers (which results in luminal inflammation) and the central role for oxidative stress on the epithelium. We suggest translation of these insights into more focus on asymptomatic smokers and early COPD, with the potential for fresh preventive and therapeutic approaches.

우리의 출발점은,

흡연으로 인해 만성폐쇄성폐질환(COPD)으로 이어지는 기도 질환의 병인(pathogenesis)과

병태생리학(pathophysiology)에 관한 비교적 새로운 연구 결과들을 전체적으로 재평가하고,

오랜 시간 검증된 전통적 개념들과 함께 “주류” 사고에 통합해야 한다는 것입니다.

치료 표적(therapeutic targets)에 대한 생각이 현재 활발히 재고되고 있는 상황에서,

기존에 받아들여진 질병 패러다임을 정교하게 다듬는 작업이 시급히 필요합니다.

우리는

기도 벽의 전반적인 “염증”이 과도하게 강조되고 있다고 생각하며,

병리의 국소적(patchy)이고 다양한(variable) 성격을 강조합니다

(그 핵심은 기도 재형성(airway remodelling)입니다).

또한,

흡연자/COPD 환자의 기도 벽 질환은

세포 감소(hypocellular), 혈관 감소(hypovascular), 파괴적(destructive), 섬유화(fibrotic) 병리를 포함하며,

상피-간엽 전이(epithelial–mesenchymal transition, EMT) 상태의 스펙트럼이

이 재형성의 중요한 동인일 가능성이 높다는 증거를 제시합니다.

더 나아가,

다양한 연구 방법론의 데이터를 종합하여 이를 폐암의 병인과 연결하고,

흡연자에서 특정 “호흡기” 세균에 의한 만성 기도 내강 집락화/감염(이로 인한 내강 염증) 및

상피에서의 산화 스트레스(oxidative stress)의 중심적 역할을 통합합니다.

우리는 이러한 통찰을

무증상 흡연자와 초기 COPD에 더 집중하는 방향으로 전환하여,

새로운 예방 및 치료 접근법의 가능성을 제시합니다.

Shareable abstract @ERSpublications

We discuss the pathogenesis and pathophysiology of COPD, emphasising their need to be reassessed as a whole and integrated with traditional concepts to refine the disease paradigm. This is urgently needed to open-up thinking about therapeutic targets. https://bit.ly/3pTyrsi

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Introduction

The authoritative source of advice and information on chronic obstructive pulmonary disease (COPD) internationally over the past 20 years has been the Global Initiative for Chronic Obstructive Lung Disease (GOLD). This was set up in 1998 with cooperation by the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health (NIH) and the World Health Organization (WHO). It has produced further comprehensive reports in 2001, 2006, 2011 and 2017–2020 [1–4]. This has transformed the COPD landscape in a positive way, with one considerable achievement being the promotion of clinical research activity leading to attempts at tailored management plans. However, there are now calls to revise the conventional prevailing approaches to this important disease, emphasising more the potential benefits and opportunities arising from anticipating the diagnosis even before classical COPD is present and enabling the treatment of COPD and even “pre-COPD” at an early stage [5–7]. We sympathise with these authors and have written this article to stimulate further positive discussion. We also build on these calls by suggesting our understanding of underlying disease processes needs to be updated to inform this discussion and future priorities. Indeed, others have recently emphasised the urgent need for this and indicated airway remodelling as a potential central issue [7]. Our intent is to systematise the balance of evidence for such a primary remodelling disease, its likely mechanisms (including interactions with airway luminal pathology) and the implications for disease management before COPD ensues, even and perhaps especially in smokers.

Introduction (서론)

지난 20년 동안 만성폐쇄성폐질환(COPD)에 대한 국제적 권위 있는 조언과 정보의 원천은

Global Initiative for Chronic Obstructive Lung Disease (GOLD)이었습니다.

GOLD는

1998년 미국 국립보건원(NIH) 산하 국립심장·폐·혈액연구소(NHLBI)와 세계보건기구(WHO)의 협력으로 설립되었으며,

2001년, 2006년, 2011년, 그리고 2017–2020년에 걸쳐 추가적인 포괄적인 보고서를 발표했습니다.[1–4]

이러한 노력은

COPD 분야를 긍정적으로 변화시켰으며,

특히 임상 연구 활동을 촉진하고 개인화된 관리 계획(tailored management plans)을 시도하는 데 큰 성과를 거두었습니다.

그러나 최근에는

이 중요한 질환에 대한 기존의 주류 접근법을 수정해야 한다는 목소리가 나오고 있습니다.

특히 고전적 COPD가 나타나기 전에 진단을 예측하고,

COPD 및 “pre-COPD”를 조기에 치료할 수 있는 잠재적 이점과 기회를 강조합니다.[5–7]

우리는 이러한 저자들의 의견에 공감하며,

더 적극적인 논의를 촉진하기 위해 본 논문을 작성하였습니다.

또한 이러한 요구에 기반하여,

기저 질환 과정(underlying disease processes)에 대한 우리의 이해를 업데이트해야 한다고 제안합니다.

이는 향후 논의와 우선순위를 결정하는 데 필수적입니다.

실제로 다른 연구자들도

최근 이러한 업데이트의 긴급성을 강조하며,

기도 재형성(airway remodelling)을 잠재적 핵심 문제로 지적한 바 있습니다.[7]

우리의 목적은

일차적 재형성 질환(primary remodelling disease)에 대한 증거의 균형을 체계화하고,

그 가능한 기전(기도 내강 병리와의 상호작용 포함) 및 COPD가 발생하기 전(특히 흡연자에서) 질환 관리의 함의를 정리하는 것입니다.

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The airway inflammation hypothesis of COPD airways

A key success of initiatives such as GOLD and COPDGene has been in promoting the assessment of clinical trajectory and severity in overt disease, emphasising airway function and more recently symptoms and acute exacerbations (AEs). Sections on pathogenesis have always tended to be less central and we propose that the strength and success of this approach, focusing on clinical disease, may have led to a relative down-playing of developments around underlying disease processes that inform design of better preventive treatments. The 2001 GOLD document [1], for example, advanced a disease model based on an abnormal airway “inflammatory response of the lungs”, with chronic inflammation involving mainly innate inflammatory activation. This inflammation was then said to damage lung tissue, so reinforcing sustained chronic inflammation and itself leading directly to COPD. “Scar tissue” involving the small airways was mentioned, with the implication that this too was due to ongoing inflammatory processes. This initial hypothetical GOLD model set the scene for all subsequent reports, which largely re-iterated this paradigm of inflammatory disease, including for emphysema referred to under the same umbrella. To an extent this proposal may well be correct, but we would suggest the refinement that much of this inflammation is in the airway lumen, this being one aspect of intermediary mediation between smoking and core remodelling disease, rather than the primary airway wall pathology itself.

An inflammation-predominant disease model of COPD has, we believe, had a major influence on respiratory cultural thinking and on its research and therapeutics agenda. However, it is notable that the GOLD model was only explicitly evidenced (with regard to two mechanistic papers [8, 9]) in 2001, neither of which really provided what could be regarded as a convincing picture of innate airway wall inflammation. Thus, in 1957, Leopold and Gough [8] observed what they termed “(post)-inflammatory fibrosis” and destruction of small airways in post mortem lungs, the inflammation being inferred from some inflammatory exudate in the lumen of their post mortem tissue samples and the thickened and purely fibrosed airway wall. In addition, Saetta et al. [9] studied lungs from smokers both with and without COPD, with the major signal in COPD found to be small airway thickening (the only cellular change in the COPD group compared to the other smokers being an increase in CD8+ lymphocytes). Notably, there was no suggestion of an increase in macrophages or neutrophils in the airway wall tissues.

Our group extensively reviewed this issue in 2017 [10] and concluded that evidence for this inflammatory hypothesis in any broad sense is minimal. We do not intend to review this literature again here, as this review is intended to be an update and follow-up to that previous document. However, Eapen et al. [11] published what could be regarded as a uniquely comprehensive analysis of airway wall cellular content in the same year and this did not support (and indeed ran counter to) the airway wall inflammation narrative, at least in any conventional sense and especially in the small airways. Furthermore, this was one of the very few such studies that included a normal control population and total cell counts by sublayer in the airway wall, as well as reporting all inflammatory/immune cell types by both absolute number and percentage of total. The most striking feature of airway wall cellularity throughout the bronchial tree in COPD was hypocellularity. This was quite marked, with a 50% reduction in total cells in smoker COPD in the large airways and 30% in the small airways (figure 1, where the larger left-hand chart represents the normal cellular pattern and the smaller right-hand chart the fewer cells of the relatively hypocellular COPD small airway wall). In fact, this replicated an earlier independent analysis, albeit one performed for a different purpose [12]. There are some subtle differences in cells between the large and small airways, and subtle changes in “inflammatory” cells in percentage terms in COPD; however, the only significant change in absolute cell counts was again in CD8+ lymphocytes. Eosinophils were highly variable between individuals and sites, and much fewer in number than other cell types in what was a typical and non-asthma-hybrid COPD group. Such counts were not obviously different from normal and, as such, eosinophils were not reported due to the poor and uncertain signal. Very importantly, all cellular changes in COPD airways were undoubtedly present as a feature of smoking per se, with only a small extra signal in COPD at most, at least in mild–moderate disease.

COPD 기도의 염증 가설

GOLD나 COPDGene과 같은 이니셔티브의 주요 성공은 

명백한(obvert) 질환에서 임상 경과와 중증도를 평가하는 것을 장려하고,

기도 기능, 최근에는 증상과 급성 악화(AEs)를 강조한 데 있습니다.

그러나 

병인(pathogenesis)에 대한 섹션은 항상 상대적으로 덜 중심적이었으며,

우리는 이러한 임상 중심 접근법의 강점과 성공이 

예방 치료 설계를 위한 기저 질환 과정에 대한 발전을 상대적으로 소홀히 하게 만들었을 가능성이 있다고 제안합니다.

예를 들어 2001년 GOLD 문서[1]는 

비정상적인 기도 “폐의 염증 반응”을 기반으로 한 질병 모델을 제시했으며,

주로 선천성 염증 활성화를 동반한 만성 염증을 강조했습니다.

이 염증이 폐 조직을 손상시켜 지속적인 만성 염증을 강화하고,

결국 직접 COPD로 이어진다고 설명했습니다.

소기도에 관련된 “반흔 조직(scar tissue)”도 언급되었으며,

이는 지속적인 염증 과정에 의한 것이라는 함의를 담고 있었습니다.

이 초기 가설적 GOLD 모델은 이후 모든 보고서의 기반이 되었으며,

폐기종(emphysema)까지 포함해 염증성 질환 패러다임을 대체로 반복했습니다.

이 제안이 어느 정도는 맞을 수 있지만,

우리는 이 염증의 대부분은 기도 내강(airway lumen)에 존재하며,

이는 흡연과 핵심 재형성 질환 사이의 중간 매개 과정의 한 측면일 뿐, 

일차적인 기도 벽 병리 자체는 아니다라는 정교화(refinement)를 제안합니다.

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우리는 염증 우세 모델(inflammation-predominant disease model)이 호흡기 의학계의 사고, 연구, 치료 의제에 큰 영향을 미쳤다고 믿습니다. 그러나 주목할 점은 GOLD 모델이 2001년에야 두 편의 기전 논문[8,9]을 근거로 명시적으로 제시되었고, 그중 어느 것도 선천성 기도 벽 염증에 대한 설득력 있는 그림을 제공하지 못했다는 것입니다.

1957년 Leopold과 Gough[8]은 사후(post mortem) 폐에서 “(후)염증성 섬유화(post-inflammatory fibrosis)”와 소기도 파괴를 관찰했으나, 염증은 샘플의 내강에 있는 염증성 삼출물과 두꺼워지고 순수하게 섬유화된 기도 벽으로부터 추론된 것이었습니다. 또한 Saetta 등[9]은 COPD 유무 흡연자의 폐를 연구했는데, COPD에서 주요 신호는 소기도 비후(small airway thickening)였으며 (다른 흡연자에 비해 COPD 그룹에서 유일하게 증가한 세포 변화는 CD8+ 림프구 증가), 기도 벽 조직에서 대식세포나 호중구 증가를 시사하는 내용은 없었습니다.

우리 연구팀은 2017년에 이 문제를 광범위하게 검토[10]하여, 광의의 염증 가설을 뒷받침하는 증거가 미미(minimal)하다고 결론지었습니다. 본 리뷰는 그 이전 문헌의 업데이트·후속이므로 해당 문헌을 다시 검토하지 않겠습니다.

그러나 같은 해 Eapen 등[11]은 기도 벽 세포 함량에 대한 독보적으로 포괄적인 분석을 발표했으며, 이는 (특히 소기도에서) 기존의 기도 벽 염증 서사(narrative)를 지지하지 않았고 오히려 반대되는 결과를 보였습니다. 이 연구는 정상 대조군을 포함하고, 기도 벽의 하층별 총 세포 수와 모든 염증/면역 세포 유형을 절대 수와 백분율로 모두 보고한 몇 안 되는 연구 중 하나였습니다.

COPD에서 기관지 전체에 걸친 기도 벽 세포 밀도의 가장 두드러진 특징은 hypocellularity(세포 감소)였습니다. 이는 상당히 뚜렷하여, 흡연 COPD 환자의 대기도에서는 총 세포 수가 50% 감소, 소기도에서는 30% 감소했습니다(그림 1: 왼쪽 큰 차트는 정상 세포 패턴, 오른쪽 작은 차트는 COPD 소기도의 상대적 세포 감소 상태). 이는 이전의 독립적 분석을 재현한 결과이기도 합니다.[12]

대기도와 소기도 사이에는 세포 구성에 미묘한 차이가 있고, COPD에서 “염증” 세포의 백분율에는 미묘한 변화가 있지만, 절대 세포 수에서 유의미한 변화는 다시 CD8+ 림프구 증가뿐이었습니다. 호산구는 개인과 부위에 따라 매우 다양했으며, 전형적인 비천식-혼합형 COPD 그룹에서는 다른 세포 유형보다 훨씬 적었고 정상과 뚜렷한 차이를 보이지 않아, 신호가 약하고 불확실하여 보고되지 않았습니다.

매우 중요한 점은 COPD 기도의 모든 세포 변화가 흡연 자체(per se)의 특징으로 나타났으며, COPD(특히 경증~중등증)에서는 기껏해야 작은 추가 신호만 있다는 것입니다.

FIGURE 1

Total cell counts and absolute/percentage values for cell types in the small airways of normal never smokers and currently smoking chronic obstructive pulmonary disease (COPD) subjects (COPD-CS subjects). The changes evident in COPD are in fact mainly smoking-related [11, 14]. The size of the pie-charts corresponds to the total cell counts (non-scaled). CS: cigarette smoke.

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One potentially important and rather different report that might unsettle this conclusion on the airway wall, at least regarding COPD itself, was that of Polosukhin et al. (2017) [13]. Whole lungs were obtained from clinical transplant services for both normal control tissue and ex-smoker severe (stage 3–4) COPD tissue. As in our own small airway studies, for stage 1–2 COPD they obtained lung resection material from ex-smokers with lung cancer. No actively smoking COPD subjects or actively smoking non-COPD subjects were included. Using low power magnification for assessment they found patchy disease that affected some airways and not others, and which was more common in more severe stages of disease compared with milder disease. In terms of inflammation, they described neutrophil and macrophage increases that were especially marked in severe disease. These were mostly in the form of peripheral cuffing around the airways in the adventitial layer and the parenchymal lung beyond this, but only in patches where remodelling was also present. Although this may prove to be a highly significant paper, no one else has (to our knowledge) described such marked peripheral inflammatory findings. This applies even to Leopold and Gough [8] in their original detailed descriptions of airway disease in centrilobular emphysema. We would agree with the patchy nature of COPD small airway disease and, when averaged, many remodelling indices have wide group confidence limits and overlap with normal controls in a manner that is consistent with this. Furthermore, human studies of inflammatory cells in the airway wall in COPD have largely been solely about cell profiles. Thus, it is possible that subtle changes in function could be important pathogenically, even with normal cell numbers [11, 14].

Airway remodelling as the primary disease in COPD airways

Airway wall tissue remodelling was first noted early in research into smoking and COPD pathology, with changes to the epithelium (such as goblet cell hyperplasia and squamous metaplasia) [15, 16] accompanied by submucosal (below the muscle layer) mucous gland hyperplasia. However, there is unanimity in the subsequent literature that the most outstanding change in airway resistance in COPD occurs not with these ubiquitous smoking-related epithelial changes but with wall thickening and narrowing, most importantly in the small airways (those of <2 mm internal diameter) [17–19]. Despite the physiological resistive consequences being peripheral, all these pathological remodelling changes occur throughout the airway tree and in smokers as well as in COPD subjects. As an aside, the increase in resistance occurs primarily in the middle-sized airways in asthma due to muscle thickening, but becomes peripheral in asthmatic subjects who smoke [20].

In smokers, the first physiological consequences are a decrease in forced vital capacity (FVC) secondary to air trapping and encroachment by increasing residual volume (RV), all due to fixed small airway narrowing [21–23] and air trapping in the surrounding lung. More insights into the crucial role of small airway remodelling in COPD came from the early observations that, as well as wall thickening, the remodelling process involved obliteration of small airways, occurring even before the forced expiratory volume in 1 s (FEV1)/FVC ratio began to change [19]. This was confirmed later in studies using micro-computed tomography (micro-CT) techniques, indicating that 40% or more of small airways had disappeared even in apparently earliest-stage COPD [23, 24]. This means that the very ontological designation of COPD, based on a rather arbitrary FEV1/FVC ratio (<70%), needs updating [5] to avoid underestimating disease burden in smokers.

COPDGene has pointed out how heterogeneous the trajectory to COPD really is [6]. Furthermore, since the conventional transition point is actually quite late in the pathogenic process and given that FEV1 is predominantly a large airway flow index while FVC itself decreases with air trapping, the FEV1/FVC ratio is hardly an optimal measure of deteriorating small airway function. Indeed, in the Australian Burden of Obstructive Lung Disease (BOLD) [25] study, which used the degree of scalloping of the mid to distal part of the descending limb of the spirometric flow–volume curve as an appropriate index of small airway narrowing/obliteration, 25% more significant airway obstruction was detected in the general community.

Thus, one of our main points (now also made by many others [5–7]) is that the focus for prevention and treatment should be more on “smoking-related airway disease” even before progression to COPD, or indeed even before symptoms. Thus, even totally asymptomatic smokers may be in urgent need of secondary prevention measures, especially if they are on a rapid downhill trajectory. While this is frequently inferred it is not in the official guidelines and as such is not yet culturally embedded.

Before moving on, we feel it would be worthwhile to specifically address three pertinent matters. First, the paper perhaps most quoted in defence of the inflammatory model of COPD pathogenesis is probably that from Hogg et al. [26]. Again, the outstanding feature emphasised was airway wall remodelling, but the paper seems more remembered for its small airway wall inflammatory cell profiles in lung resection material. These were from COPD patients only, with no normal or smoker-normal controls. A quite novel technique was used which detected inflammatory-type cells only in a minority of airways in early COPD; thus, only 40% of all airways contained any neutrophils or macrophages and 20% had CD8+ lymphocytes. This patchiness is again rather reminiscent of the study by Polosukhin et al. [13], although their cellular findings were very different (in a quantitative cell analysis of the minority of airways containing inflammatory cells, their only significant signal was for CD8+ lymphocytes and then only in the most severe groups (GOLD 3–4 together)). They further described, again in the most severe COPD only, aggregates of B-cells that were suggested as likely secondary to chronic infection in end-stage disease. Notably, in a rather earlier study [27], our group described such bronchus-associated lymphoid tissue (BALT) aggregates in the airways, with surrounding T-cells and hypervascularity, even in normal subjects (although they were especially common in smokers even without COPD). There has been substantial emphasis given to formulating the pathological picture of COPD based on data from severe disease [13, 26]. However, it is of interest that the BOLD study emphasised that such end-stage (grade 3–4) disease occurs in only about 2% of all the COPD in the general population [28]. Thus, as also recently suggested by others [7], we feel that studies on the pathogenesis of COPD would be better focused on early disease and, vitally, on smokers before overt clinical disease appears (where arguably the most important action is to be found).

Secondly, what about bronchoalveolar lavage (BAL)/sputum data? In general, it is accepted that the literature suggests a signal in the airway lumen for innate immune activation, with an increase in macrophages and neutrophils and, in a minority of cases, also in eosinophils (again more in smokers than specifically in COPD cases). Cellular constituents vary quite a lot between BAL and sputum samples, with the former representing peripheral airways and the latter more central airways. Furthermore, at least two independent and thorough reviews of the literature have shown that evidence for the “COPD luminal inflammatory supposition” is rather less certain and more variable than might be generally supposed, even during AEs [10, 29]. One of the issues, especially with sputum, is the presentation of data as percentages of cell-types only [30], without any absolute counts. This makes interpretation difficult because if one cell-type becomes more frequent others must seem fewer, but actually may not have changed at all or may even have increased in absolute number. In addition, one cell-type may seem prominent even when there are actually fewer total cells present. Even so, this approach does seem to have proved useful in discriminating those eosinophil-dominant airways that are responsive to corticosteroid therapy [30] and, in a recent study [30], has proved to be empirically robust enough to show variation in cell percentages related to the molecular microbiome (although this too of course is also semi-quantitative and based on percentage representation of microbe types without reference to quantity).

Thirdly, what about emphysema? GOLD, and especially its 2017 report [4], linked airway and lung parenchymal disease as coincident in pathogenesis and timing. Thus, COPD is “a mix of small airway disease and emphysema due to chronic inflammation” where “inflammation causes (these) structural changes”. In fact, there is now very substantial, even clinching, evidence from computer-assisted high-resolution computed tomography (HRCT) lung scanning initially and from voxel-wise parametric response mapping (PRM)-CT scanning subsequently, and also from CT analysis of the morphology of resected lung tissue, that there is very much more small-airway disease present than emphysema (overwhelmingly so in early COPD). Longitudinal studies have confirmed that airway disease precedes parenchymal destruction and indeed that emphysema in smokers occurs where there has been secondary air trapping [24, 31–36].

Epithelial–mesenchymal transition and insights into its role in driving airflow obstruction

Epithelial–mesenchymal transition (EMT) is a conserved, fundamental, reversible, biological mechanism underlying embryogenesis/organ development (type 1), wound healing and fibrosis (type 2), and cancer development and progression (type 3) [37, 38]. EMT was first postulated as active in human airway disease in 2004 by the Newcastle UK Lung Transplant Group [39–41], as part of the development of bronchiolitis obliterans syndrome (BOS) in chronic rejection [41, 42]. The development of BOS involves airway epithelial injury from a number of causes and, although more sub-acute, resonates with known elements of COPD pathophysiology. This led to a collaborative investigation of the possibility of EMT being active and pathogenic in the airways of smokers with and without COPD. Over the past decade such investigations, from an increasingly large number of centres (including from ourselves) and using increasingly powerful technologies, have largely supported this hypothesis [43]. However, although widely cited in recent reviews on COPD, this work has yet to be fully endorsed in the literature [44, 45].

A seminal paper by Crystal et al. [46] provided evidence that gene reprogramming in airway epithelial basal/stem cells may be a fundamental factor in the development of COPD and this would include well-accepted changes such as squamous cell and goblet cell hyperplasia. We suggest that EMT should be included on that list, which fits with an observation that, as well as being structurally and functionally altered (as described over 60 years ago [15]), there was another prominent feature related to the airway epithelium in smokers and in COPD. Namely that the reticular basement membrane (RBM) immediately below the epithelium's thin true basement membrane (BM) in COPD was not just thickened (as in asthma) but also fragmented, with cell-containing clefts within it, which we realised was a well-accepted classic marker for EMT generally [47]. Confirm‎ing the presence of active EMT, we have also shown that both the basal epithelial and RBM cleft cells in smokers stain positively (especially in COPD subjects) for widely used mesenchymal EMT markers such as S100A4, vimentin and α-smooth muscle actin (α-SMA), as well as epithelial markers [48].

A series of further clinico-pathologic studies have shown that transforming growth factor-β (TGF-β) is likely to have a major EMT-inducing role, working through both its canonical and alternative pathways to activate well-described EMT-specific transcription factors [49, 50], although this is probably along with other growth factor EMT-drivers (table 1 and figure 1). We feel that these findings of reprogrammed airways with active EMT are consistent with and complimentary to the earlier findings of large numbers of destroyed airways even in pre-COPD [31]. Therefore, by definition, our research has been looking at “survivor” airways but has likely been showing the fundamental active pathogenic processes of ongoing small airway wall myofibroblast accumulation, marked wall sub-layer thickening and matrix changes related to luminal narrowing [51]. Ultimately, this would be predicted to lead to luminal obliteration over time, consistent with the important literature from Hogg et al. [31].

TABLE 1

A summary of selected common stimuli, signalling pathways and transcription factors (TFs) associated with epithelial–mesenchymal transition [37, 38]

Selected stimuli

Signalling pathways

TF

TF type

The Snail, Twist and ZEB TF families control cell–cell adhesion, cell migration and extracellular matrix (ECM) degradation. They have been shown to have evolutionarily conserved roles in epithelial–mesenchymal transition (EMT) in different biological settings and in a range of organisms. TGF-β: transforming growth factor-β; EGF: epidermal growth factor; VEGF: vascular endothelial growth factor; HGF: hepatocyte growth factor; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; ZEB: zinc finger E-box-binding homeobox; SIP: Smad interacting protein. #: TGF-β (the classic, positive control in in vitro EMT experiments) activates Smad2 and Smad3 and complexes with Smad4, which then interacts with DNA-binding TFs inducing EMT; an alternative pathway operates via β-catenin released when intercellular adhesion breaks down; ¶: activated by EGF-receptor stimulation for example; +: the Wnt pathway causes cytoplasmic β-catenin accumulation and nuclear translocation to act as a TF co-activator; §: Notch signalling activation occurs via cell to cell contact with ligand expression‎ in signal-providing cells (dysregulated in the epithelium of COPD patients); ƒ: EMT/lung cancer are linked to the Hedgehog signalling pathway, which is modulated by cigarette smoke.

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A further important novel observation has been that in damaged smoker/COPD airways both the RBM and even the epithelium itself are hypervascular (consistent with type 3 cancer-related EMT), at least in the larger airways. Notably, this feature contrasts with the hypovascularity which accompanies the hypocellularity of the underlying thickened lamina propria [52, 53].

Other groups have also demonstrated EMT in COPD airways and there have been >100 papers in PubMed on this subject in the last decade, mainly in the last 5 years. To quote just one of these, Gohy et al. [54] used complimentary primary airway epithelial cultures and airway biopsies from COPD patients to show that the bronchial epithelium from the conducting airways of COPD patients exhibited increased mesenchymal vimentin expression‎ with decreased epithelial ZO-1 and E-cadherin protein expression‎, consistent with EMT in vivo. The increase in vimentin expression‎ correlated with BM thickening and airflow limitation. Importantly, the mesenchymal features of the COPD epithelial cells in vivo were “recapitulated” in ex vivo air–liquid interface cultures. The air–liquid interface process involves cell expansion in culture and passage, so this demonstrates a strong imprinting of the COPD airway epithelial gene fingerprint despite being removed from injury and the airway milieu.

Chronic smoking seems to interact with a range of other airway damaging factors in activation of epithelial EMT. The ECLIPSE study [55] found that the second-best predictor of COPD exacerbations was a patient history of gastroesophageal reflux, likely linked to micro-aspiration. Of relevance to this, Chen et al. [56] showed that coincident expression‎ of (bile acid) farnesoid X receptors (FXR) and EMT markers was significantly elevated in the small airway epithelium of COPD patients and was related to airflow obstruction. In a similar vein of extraneous interactions with a highly relevant COPD comorbidity, a recent paper from Wu et al. [57] indicated that high glucose tensions combined with cigarette smoke (CS) challenge induced EMT in a rat model of diabetes and in cultured human airway cells, and that patients with COPD and diabetes had worse airway obstruction than COPD patients without diabetes.

Although the details are beyond the scope of this article, associations of COPD with lung cancer specifically (even allowing for smoking) are well accepted and of high clinical and epidemiological significance. This association has also increasingly been linked with EMT and its known drivers such as TGF-β1 (table 1) [58–61]. Chronic fibrotic processes are generally strongly associated with epithelial cancer formation, again with TGF-β1-induced EMT intimately implicated in that association (the so-called “wound healing, chronic fibrosis and cancer progression triad”) [62, 63]. A novel clinical pathology study by Mahmood et al. [64] has directly related prognostic EMT activity in nonsmall cell lung cancers with that in the same patients' non-cancerous airways.

Of human cancers, 95% are of epithelial origin and EMT is increasingly regarded as being inherent to epithelial cancer development in general, as well as metastasis, poor prognosis and drug resistance [64]. Fortunately, promising anti-EMT drugs are now being developed to inhibit these processes in a wide number of specific tumours, with the promise of better clinical outcomes [65–73]. As such, novel therapy for EMT in COPD is also potentially feasible.

How do studies on the genetics of COPD and on airway ageing add to this picture?

A number of somatic genes have been implicated in COPD, although mainly as a relatively small contribution to emphysema with (small) airway disease per se being very much less studied, mainly because of the difficulty in specifically phenotyping it radiologically or physiologically [74]. The only gene strongly associated with the non-emphysema phenotype of COPD (i.e. airway disease) is FAM13A on chromosome 4q22 [75], which seems especially related to instability of cell–cell adhesion resulting in release of β-catenin into the cell cytoplasm, a well-known, strong stimulus to EMT and tissue fibrosis.

In a systems biology approach, Wang et al. [76] recently described mutual gene expression‎ profiles and genetic interaction networks for the bronchial epithelium and lung cancer. One standout active gene was TBL1XR1, which is involved in the epigenetic interaction between histones and EMT-like activity, and myofibroblast proliferation, with high activity relating to poor squamous lung cancer survival as well as to risk of COPD. Paradoxically, in terms of current medications for asthma/COPD, a risk factor for both COPD and lung cancer is upregulation of the ADRB2 gene for sympathetic β2 receptors, with downregulation of this gene activity associated with better squamous-cell cancer survival [76]. Using 3D epithelial cell culture, Matsumura et al. [77] exposed cells to oxidant stress and found 15 genes were perturbed, with those for cell proliferation and redox homeostasis being downregulated; however, EMT-related genes (including for epidermal growth factor receptor (EGFR)) were upregulated and this was especially marked in cells from smokers and COPD patients.

In an analysis of epigenetic methylated gene profiles as an index of gene upregulation, Kachroo et al. [78] found that in COPD tissue there was a prominence of gene methylation associated with the TGF-β, Wnt, Notch and Hedgehog EMT-signalling pathways, including phosphoinositide 3-kinase (PI3K)–protein kinase B (Akt), a kinase closely related to EMT activation [79].

In their recent review of genetics in COPD, Silverman et al. [74] emphasised increasing current interest in COPD and single nucleotide polymorphism (SNP)-based allelic variants. As an example, Zhao et al. [80] showed a strong COPD risk associated with the C1562T allelic variant of the matrix metallopeptidase (MMP)-9 gene. MMP-9 expression‎ in the epithelium is a strong signal for EMT activity, as it is involved in digesting a pathway though the RBM for motile mesenchymally transitioning epithelial cells. Similarly, Devries and Vercelli [81] provided strong evidence for involvement of variants in TGF-β pathway genes in COPD. Indeed, particularly disadvantageous alleles of (anti-oxidant enzyme) glutathione S-transferase (GST) genes favour loss of airflow with even low amounts of oxidising pollution [82, 83].

The concept that COPD may represent an acceleration of a genetically determined normal lung ageing process has gained traction following a mainly hypothesis-generating paper by Sandfords et al. [84]. This showed that cultured epithelial cells stressed by CS extract produced a senescence marker, β-galactosidase and that alveolar type 2 cells from emphysematous lung tissue demonstrated tell-tale shortened telomeres, as did blood leukocytes from the same individuals. Later, shorter telomere length was related to increased morbidity and mortality in COPD [85]. However, the picture has become far from clear and indeed quite complex, with studies of polymorphisms of classic ageing genes (namely TERT, DSP and FAM13A) showing a picture typical of senescence with reduced expression‎ in idiopathic pulmonary fibrosis (IPF) lungs, but paradoxically anti-senescent high expression‎ in both COPD and lung cancer [86]. There was however a muted and partial pattern of senescence observed rarely in emphysema. These “inverse-senescence” genetic traits in (airway) COPD/cancer would slow cell turnover, decrease apoptosis and increase cell longevity. All of these functional cell changes would allow extra time for accrued DNA damage to present as malignant transformation and would also have a pro-EMT/airway fibrosis effect [86].

In a recent review, Occhipinti et al. [87] catalogued the known consensus radiological features of the ageing lung: large airway wall thinning, large and medium sized airway luminal dilatation, air trapping, decreased cillial function, increased luminal secretion, alveolar dilatation with decreased surface area, reduced lung vessels (with preserved ventilation (Vʹ)/perfusion (Qʹ) matching) and finally an increase in linear and reticular shadowing. Emphysema (i.e. alveolar destruction) was not feature and nor was airway wall thickening. Indeed, airways were thought to be abnormally compliant, as were lung parenchyma [87]. One study reviewed in this latter article reported data on 4th to 6th generation airways using computer-assisted HRCT lung scanning [88] in healthy, non-smoking subjects aged 60–90 years, with air trapping being the most prominent feature. This would most likely be due to small airway dysfunction but there was no evidence of distal airway thickening. There was also dilatation of mid-sized airways. A later HRCT study [89] provided quantitative information on airways down to 3.5 mm external diameter in healthy individuals, but only up to an age of 55 years. It found progressive full-length airway wall thinning with age, although in contrast it found generalised airway thickening in smokers.

Finally, using a novel method of endobronchial optical coherence tomography, Su et al. [90] showed that the morphology of the normal airway did change with age between 20 and 69 years of age, with thinning of cartilage and dilatation of the airway in middle age (with secondary narrowing after the age of 55 years), but with no apparent change in airway wall thickening.

Taking all this information together, it seems most likely that although there may be some overlap, COPD is not just accelerated ageing but a distinct and quite specific pathological process, one that is linked to lung cancer. One feature of COPD that does definitely overlap with airway ageing is air trapping; however, in normal ageing this is likely to be due to decreased lung elastic recoil and also perhaps greater compliance of the airways themselves. By contrast, the main and certainly early physiological problem in COPD is small airway thickening, luminal narrowing and destruction. Thus, COPD seems most likely to be a disease “in” the ageing process, rather than “of” it per se. Indeed, COPD pathology seems to shift the natural senescence history of the lung largely in a different yet disastrous direction.

Infection as a driver of airway luminal inflammation and epithelial activation

Recurrent microbial infection and/or colonisation of the airway with bacteria, viruses or both together remains a crucial symptom-generating part of COPD and especially AEs. Indeed, infections are linked to approximately 85% of AEs [55]. However, aside from symptoms and exacerbations, chronic airway luminal infection/colonisation in and of itself results in increased chronic morbidity and mortality [91].

As documented extensively, the most frequent micro-organisms isolated from the lower respiratory tract of even asymptomatic smokers and of persistently colonised COPD patients are non-typeable Haemophilus influenzae (NTHi), Streptococcus pneumoniae and Pseudomonas aeruginosa (though the latter is mainly seen in the more severe stages) [91, 92]. Furthermore, NTHi is also the bacterial pathogen most frequently isolated from patients with AEs of COPD [93, 94]. Colonisation of the lower respiratory tract by these “classic/typical” respiratory bacterial pathogens is also associated with an increase in daily symptoms and increased sputum interleukin (IL)-8 levels [95], as well as very importantly being a driver of accelerated decline in FEV1 [96].

A number of possible mechanisms underlying this major airway bacterial infection problem in COPD have been suggested, mainly a hypothesised “immune defect” (such as a focal decrease in epithelial surface secretory IgA) [13] or smoking-induced high oxidative stress (and/or epithelial barrier dysfunction) [97]. We have highlighted another pathogenic pathway, the absolute need for microbes to adhere to serendipitous receptors on the airway epithelium before they can colonise/infect/invade. We have found that the known major binding receptor for all these classic respiratory bacteria to adhere, platelet-activating factor (PAF) receptor, is significantly upregulated in expression‎ in the epithelium of both the large and small airway epithelia in smokers and even more so in those with COPD. Moreover, PAF receptor expression‎ is strongly associated with the scale of smoking history [98, 99]. Furthermore, none of these mechanisms need be mutually exclusive.

In the airways, PAF itself may modulate host inflammation [100–102]; however, PAF receptor upregulation seems to be utilised coincidentally as a convenient and abundant adhesion site in smokers for all the major respiratory bacterial pathogens highlighted above [103]. Furthermore, blocking PAF receptor with specific receptor antagonists counters the epithelial adhesion of H. influenzae, S. pneumoniae and P. aeruginosa in cultured lung epithelial cells [104, 105]. The adhesion of these bacteria to PAF receptor is due to them all having, quite unusually and serendipitously, the molecule phosphorylcholine (ChoP) as a binding site precisely positioned enzymatically in their outer lipopolysaccharide layer [106]. In addition, variation in ChoP genes through epigenetic control relates to bacterial pathogenicity [107, 108].

These “microbial adhesion” insights have led us to a general proposal for further clinical assessment of non-antibiotic approaches to the inhibition of microbial pathology, for both bacteria and viruses, by inhibiting their adhesion to the respiratory mucosa [109]. Drugs already available, such as the PAF receptor blockers trialled as anti-asthma therapies over 25 years ago, could potentially be useful here and could be used as prevention/prophylaxis treatments or in the initial phases of AEs.

Finally, persistence of low-grade airway luminal inflammation secondary to chronic infection and its generated reactive oxygen species (ROS), or the microbes themselves, may well drive epithelial activation, gene reprogramming and TGF-β1, tumour necrosis factor-α (TNF-α) and Wnt production, which then drive EMT activation [109–111] (figure 2). This suggests an integrated model of such drivers in the lumen that is intimately involved with what happens to the epithelium and through it to the tissues below where the directly obstructive pathology occurs.

FIGURE 2

Schematic of epithelial–mesenchymal transition (EMT) in cigarette smoke (CS)-related chronic obstructive pulmonary disease (COPD). Chronic CS exposure leads to alteration of the airway luminal environment (e.g. oxidants, infection and inflammation). The increase in reactive oxygen species (ROS) activates the respiratory epithelium, with an increase in transforming growth factor-β (TGF-β) as well as other EMT-driver production. In turn, this activates basal cell cytoplasmic signalling (via Smads, STATs, β-catenin and kinase reactions), to produce further nuclear transcription factors (such as Twist, Snail, Slug and ZEB). All this activity leads to the initiation of transition of basal cells into mesenchymal cells, rather than the normal/abnormal epithelial phenotype. This results in proliferation of myofibroblasts which then markedly increase secretion of both standard and abnormal extracellular matrix (ECM) proteins, leading to airway thickening/obliteration and subsequent airflow limitation. TF: transcription factor; RBM: reticular basement membrane; STAT: signal transducer and activator of transcription; ZEB: zinc finger E-box-binding homeobox.

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Potential role of oxidant stress

The oxidation of critical and potentially damaging cellular molecules in smokers' airways by ROS and other acute phase oxidants is, as in other tissues, dealt with through the antioxidant glutathione and the multifaceted GST enzyme system. This is responsible for the S-glutathionylation of potentially damaging oxidised reactive electrophilic centres on a wide variety of substrates, such as thiol groups on protein/enzyme cysteine residues and lipid peroxidation sites, in order to make the compounds more water soluble to aid detoxification and elimination from the cell. GSTs also have an important separate role in control of the complex kinase cellular systems involved in vital functions such as cell proliferation, apoptosis and EMT [112]. Indeed, this system seems to be a vital link between ROS-induced oxidant stress on epithelial basal cells, TGF-β production, induction of EMT with fibrosis and also malignancy. The GST system is negatively controlled by another enzyme, glutaredoxin and its deficiency in epithelial cells has been shown to increase activation of the TGF-β pathway and increase airway fibrotic remodelling [112]. GST gene polymorphisms have also been mentioned as favouring loss of airflow [82, 83].

Conclusions: relevance of this model to therapeutics in COPD

As we have shown, it is hardly a novel proposition that the key underlying features of COPD (and also of smokers in pre-COPD) are airway wall tissue remodelling and thickening, and ultimately loss of a large number of small airways. However, we do appreciate that pathologies in the airway lumen induced by CS, including inflammation and oxidant stress, may well be important as intermediary determinants of epithelial activation to set this process off. Overall, we would encourage future guideline statements to reappraise the totality of evidence on pathology and ponder how this integrated whole could change the focus of the suggested management strategies, especially if we can nominate relevant pathogenic pro-fibrotic processes as targets. An overview model of what we think are such a broad set of COPD-related processes is given in figure 3.

FIGURE 3

Overall pathogenesis of chronic obstructive pulmonary disease (COPD). Primary phenomena include airway luminal cellular inflammation (due to chronic infection with “respiratory pathogens” and/or cigarette smoke (CS)-induced oxidative burden) and fibrosis and obliteration of the small airways, as well as remodelling changes including squamous metaplasia and mucus hypersecretion, and goblet-cell hyperplasia in the large airways. These changes together are ultimately associated with daily symptoms, risk of acute exacerbations of COPD (AECOPDs), economic burden and decreased quality of life (QoL). Basal cells in the airway epithelium are increasingly regarded as extremely important in airway remodelling in all its forms, including those resulting from epithelial–mesenchymal transition (EMT) and angioneogenesis. Secondary phenomena include emphysema (enlargement and destruction of terminal bronchioles and alveoli) and lung cancer, likely related to EMT.

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We have, in particular, shown that EMT plays a major (and possibly fundamental) final pathway role in COPD (small) airway remodelling disease. EMT is now increasingly being considered as treatable, at least in oncology [65–73], while in IPF anti-fibrotic drugs (such as nintedanib and pirfenidone) [113] have been introduced with effect. All of these drug modalities hold great promise for translation to COPD; however, drugs already used in COPD may themselves have an anti-EMT effect, either directly and/or through damping innate luminal inflammation and related secondary ROS attack. It is notable that inhaled corticosteroids (ICS) have been suggested as being both protective in lung cancer [114] and specifically inhibitory of EMT in human airways [115]. Long-acting β-agonists (LABAs), long-acting muscarinic antagonists (LAMAs) and phosphodiesterase (PDE)-inhibitors may also contribute to a direct anti-EMT effect [113, 116], as might urokinase-type plasminogen activator receptor (uPAR) inhibition [117]. In the same vein, statins have long been thought of as potentially useful in COPD, both in terms of morbidity and mortality, but have been shown not to help in regard to frequency of exacerbations [118]. They also decrease lung cancer risk [119] while being shown to reduce EMT activity and through this cancer aggressiveness [120]. Designer small molecules which inhibit the epigenetic reader BRD4 have been shown to switch off EMT activity and airway remodelling via a TGF-β related mechanism [121]. It may well be that our current focus on symptoms and short-term outcomes, to the detriment of long-term remodelling (as well as cancerogenic and functional outcomes in COPD), has led our research community to overlook the potential of repurposing common drugs, while maybe not utilising to its full potential its ability to trial novel drugs already in the pipeline.

We propose that with such EMT-related therapies being available, either now or in the near future, there are exciting opportunities to trial them within the emerging framework of the call for COPD management to be reviewed. We need to become more focused on detecting and managing core pathologies in at-risk individuals as early as possible and in preventing progression to clinical symptomatic disease [5–7]. Recent long-term cohort and epidemiological studies have shown that this is feasible and necessary, and they have helped us to better understand the natural history and phenotypes of both pre-COPD and established COPD [6, 7, 121, 122]. Such an approach needs a concerted push into primary care to obtain individualised spirometry baselines in early middle age and then within subsequent trajectories. Such baselines need acceptance as necessary routine screening and prevention tools, akin to those for blood pressure, cholesterol and HbA1C levels.

Within the profession we perceive an urgent need to build on the great progress made by GOLD and other initiatives, and a need to better understand and integrate the various pathologies that affect the interconnected airway lumen, epithelium and sub-epithelium (without which we cannot move forward) [7]. COPD is undoubtedly a complex disease with a number of dimensions and we need to know how all of these fit together in order to develop new conceptions of what can be achieved for our patients.

Footnotes

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References

1.  
2. 
   
   • E. Haydn Walters
   • Shakti D. Shukla 
   • Malik Q. Mahmood
   • Article
   • Figures & Tables
   • Info & Metrics
   •  
   •  
   •  
   •  
   •  
   •  
   •  
   1.  
   2. 
      
      • E. Haydn Walters
      • Shakti D. Shukla 
      • Malik Q. Mahmood
      • Article
      • Figures & Tables
      • Info & Metrics
      •  
      •  
      •  
      •  
      •  
      •  
      •  
      1.  
      2. 
         
         • E. Haydn Walters
         • Shakti D. Shukla 
         • Malik Q. Mahmood
         • Article
         • Figures & Tables
         • Info & Metrics
         •  
         •  
         •  
         •  
         •  
         •  
         •  
         1.  
         2.  
         3.