Acupuncture, Pulmonary Macrophages, and Inflammation in the Respiratory System

Macrophages in the lungs are central regulators of inflammation. They shape how strongly the body responds to infection, toxins, ischemia–reperfusion injury, and systemic immune activation. A growing body of research shows that acupuncture can modulate these pulmonary macrophages by influencing core inflammatory signaling pathways, reducing cytokine release, limiting tissue injury, and restoring lung structure and function.

This article summarizes how acupuncture affects monocytes/macrophages in different models of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and chronic airway inflammation.

1. Inhibiting TLR4–NF-κB and TLR4–MAPK Pathways in Pulmonary Macrophages

One of the key findings in the literature is that acupuncture can suppress TLR4-related inflammatory pathways in lung macrophages, thereby calming the overall inflammatory response in the respiratory system.

LI4 and the PPARγ–TLR4/NF-κB Axis in ARDS

Electroacupuncture (EA) at LI4 (Hegu) has been shown to enhance the activity of PPARγ, a negative regulator of the TLR4–NF-κB pathway. This leads to:

• Inhibition of TLR4/MyD88 signaling in alveolar macrophages.
• Polarization of macrophages from the M1 (pro-inflammatory) phenotype toward the M2 (repair-oriented) phenotype.
• Down-regulation of downstream pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6.
• Alleviation of LPS-induced acute respiratory distress syndrome (ARDS).

Through this mechanism, EA at LI4 helps prevent excessive cytokine release and reduces alveolar damage and fluid accumulation in severe acute lung inflammation.

2. ST36 and SP6 Protect the Lung from Ischemia–Reperfusion-Induced Injury

Limb ischemia–reperfusion (LIR) can trigger a surge of inflammatory monocytes and neutrophils that migrate to the lungs, causing interstitial edema and structural damage. In this context, EA pretreatment at ST36 (Zusanli) and SP6 (Sanyinjiao) has been reported to:

• Inhibit the TLR4/NF-κB pathway in alveolar monocytes/macrophages.
• Decrease expression of TNF-α, IL-1, IL-6, and myeloperoxidase (MPO).
• Reduce pulmonary interstitial edema, alveolar congestion, and bleeding.
• Restore and stabilize damaged alveolar structures.

These findings demonstrate that acupuncture can protect the lung from secondary injury triggered by distant ischemic events.

3. BL13 and ST36 Activate the Nrf2–HO-1 Antioxidant Pathway

Another important mechanism involves the Nrf2/HO-1 antioxidant pathway. EA at BL13 (Feishu) and ST36 has been shown to:

• Activate the p38 MAPK → Nrf2/HO-1 signaling pathway.
• Promote nuclear accumulation of Nrf2 and heme oxygenase-1 (HO-1).
• Reduce secretion of TNF-α, IL-1β, and IL-6 in lung tissues and plasma.
• Protect lung tissue from oxidative damage caused by excessive oxygen free radicals.

By enhancing endogenous antioxidant defenses, acupuncture helps prevent inflammatory and oxidative damage in ischemia-related lung injury.

4. Multi-Acupoint EA Protects the Lung During Cardiopulmonary Bypass

Cardiopulmonary bypass (CPB) is known to induce acute lung injury through strong oxidative stress and inflammasome activation. EA pretreatment at BL13, ST36, PC6 (Neiguan), and LI4 has been reported to:

• Modulate the p38 MAPK → Nrf2/HO-1 pathway.
• Decrease malondialdehyde (MDA), a marker of oxidative injury.
• Increase superoxide dismutase (SOD) activity, enhancing antioxidant capacity.
• Scavenge oxygen free radicals and reduce oxidative stress in lung tissues.
• Suppress NLRP3 inflammasome activation and reduce recruitment of pro-inflammatory caspase-1.
• Decrease IL-1β levels in serum and bronchoalveolar lavage fluid (BALF).
• Reduce activation of caspase-8 and caspase-3, diminishing apoptosis.

Overall, EA in this setting reduces secretion of inflammatory cytokines such as TNF-α, IL-1β, and IL-18, alleviates pulmonary fibrosis and interstitial edema, and protects lung function during and after CPB.

5. Epigenetic Regulation of Respiratory Inflammation: HDAC2 and COPD

Beyond NF-κB activation, TLR signaling in macrophages can influence histone acetylation in the nucleus, thereby regulating gene expression in nasal mucosa, respiratory epithelium, and immune cells. Epigenetic changes, such as alterations in histone deacetylase activity, are closely linked with chronic airway inflammation.

In patients with chronic obstructive pulmonary disease (COPD), reduced activity of histone deacetylase 2 (HDAC2) is associated with heightened inflammatory responses in the respiratory tract. Experimental studies show that manual acupuncture (MA) at BL13 (Feishu), BL23 (Shenshu), and Dingchuan in smoking-induced COPD rat models can:

• Increase HDAC2 mRNA and HDAC2 protein expression.
• Reduce secretion of IL-8 and TNF-α by alveolar macrophages.
• Provide a lung-protective effect with long-term improvement in airway smooth muscle function.

These results indicate that acupuncture not only modulates inflammatory signaling but also influences epigenetic regulators involved in chronic respiratory disease.

6. Summary

Across different lung injury and chronic airway disease models, acupuncture:

• Rebalances macrophage polarization from M1 to M2 phenotypes.
• Inhibits TLR4/NF-κB and MAPK inflammatory pathways.
• Activates antioxidant pathways such as Nrf2–HO-1.
• Suppresses NLRP3 inflammasome activation and downstream caspases.
• Reduces pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-18.
• Protects lung tissue from oxidative stress, apoptosis, and fibrosis.
• Regulates epigenetic factors such as HDAC2 in COPD models.

Together, these findings suggest that acupuncture provides multi-layered protection against both acute and chronic respiratory inflammation.

肺部巨噬細胞是呼吸道免疫與發炎反應的核心。它們決定身體對感染、毒素、 缺血再灌注與全身性免疫刺激的反應強度。近年研究顯示，透過特定穴位的針灸 刺激，可以調節這些肺泡巨噬細胞，抑制過度發炎與細胞激素風暴，並保護肺組 織結構。

下文整理了針灸在急性肺損傷（ALI）、急性呼吸窘迫症候群（ARDS）以及慢性 氣道發炎（如 COPD）模型中對單核細胞／巨噬細胞的調節作用。

一、抑制肺部巨噬細胞的 TLR4–NF-κB 與 TLR4–MAPK 發炎路徑

多項研究指出，針灸能抑制肺泡巨噬細胞的 TLR4 相關發炎訊號， 進而降低全身與局部的呼吸道發炎反應。

1. 合谷（LI4）：透過 PPARγ 調節 TLR4–NF-κB，改善 ARDS

電針 合谷（LI4） 被證實可提升 PPARγ（為 TLR4–NF-κB 的負向調節因子）活性，從而：

• 抑制肺泡巨噬細胞中的 TLR4/MyD88 發炎訊號。
• 促使巨噬細胞由 M1（促發炎型） 轉為 M2（修復／調節型）。
• 下調 TNF-α、IL-1β、IL-6 等促發炎細胞激素。
• 減輕 LPS 誘發的急性呼吸窘迫症候群（ARDS）嚴重度。

透過這條路徑，電針合谷有助於抑制細胞激素風暴，減少肺泡水腫與組織損傷。

二、足三里（ST36）＋三陰交（SP6）：保護肺臟免於缺血再灌注肺損傷

四肢缺血再灌注時，大量發炎細胞會被動員至肺部，引發肺間質水腫與肺泡損傷。 研究發現，電針預處理 足三里（ST36）、三陰交（SP6） 可：

• 抑制肺泡單核細胞／巨噬細胞中的 TLR4/NF-κB 訊號。
• 降低 TNF-α、IL-1、IL-6 及 MPO（髓過氧化物酶） 表現。
• 減少肺間質水腫、肺泡充血與出血。
• 協助修復受損肺泡結構，穩定肺部功能。

這說明針灸能減少遠端缺血事件所帶來的「繼發性肺臟傷害」。

三、肺俞（BL13）＋足三里（ST36）：啟動 Nrf2–HO-1 抗氧化系統

另一個重要路徑是 Nrf2/HO-1 抗氧化系統。電針 肺俞（BL13）、足三里（ST36） 可：

• 活化 p38 MAPK → Nrf2/HO-1 訊號路徑。
• 促進 Nrf2 與 HO-1 進入細胞核發揮保護作用。
• 降低肺組織與血漿中的 TNF-α、IL-1β、IL-6。
• 減少過量氧自由基對肺組織的氧化損傷。

透過增強內源性抗氧化系統，針灸可減輕缺血相關肺損傷的發炎與氧化雙重打擊。

四、多穴位電針預處理：減少體外循環（CPB）引起的急性肺損傷

心肺體外循環（CPB）常伴隨劇烈氧化壓力與發炎反應。研究顯示，在手術前以 電針預處理 肺俞（BL13）、足三里（ST36）、內關（PC6）、合谷（LI4） 可：

• 調節 p38 MAPK → Nrf2/HO-1 訊號。
• 降低 MDA（氧化損傷指標），提升 SOD 抗氧化酵素活性。
• 清除氧自由基，減少肺組織氧化損傷。
• 抑制 NLRP3 發炎小體 活化與 caspase-1 的募集。
• 降低血清與支氣管肺泡灌洗液（BALF）中的 IL-1β。
• 減少 caspase-8、caspase-3 活性，降低細胞凋亡。

綜合來看，電針在此情境下可減少肺組織與血漿中的 TNF-α、IL-1β、IL-18，緩解肺纖維化與間質水腫，保護肺功能。

五、COPD 中的表觀遺傳調控：HDAC2 與針灸

TLR4 發炎訊號除了活化 NF-κB，也會影響巨噬細胞核內的 組蛋白乙醯化，進而改變鼻黏膜、呼吸道上皮與免疫細胞的基因表現。 在慢性阻塞性肺病（COPD）中，HDAC2 活性下降與慢性呼吸道高發炎 密切相關。

研究顯示，在吸菸誘導的 COPD 大鼠模型中，針刺 肺俞（BL13）、腎俞（BL23）、定喘 可：

• 上調 HDAC2 mRNA 與 HDAC2 蛋白 表現。
• 降低肺泡巨噬細胞分泌的 IL-8 與 TNF-α。
• 長期改善氣道平滑肌功能，對慢性呼吸道發炎具有保護作用。

這顯示針灸不僅調整免疫訊號，還能透過表觀遺傳機制介入慢性氣道疾病。

六、小結：針灸對急性與慢性呼吸發炎的多層次保護

綜合上述不同實驗模型，針灸在呼吸系統發炎中的作用可概括如下：

• 調節巨噬細胞由 M1 轉向 M2 型，平衡發炎與修復。
• 抑制 TLR4/NF-κB 與 MAPK 等核心發炎路徑。
• 啟動 Nrf2–HO-1 抗氧化系統，減少氧化壓力。
• 抑制 NLRP3 發炎小體與下游 caspase 活化。
• 降低 TNF-α、IL-1β、IL-6、IL-18 等促發炎細胞激素。
• 減少肺組織的氧化損傷、細胞凋亡與纖維化。
• 調控 HDAC2 等表觀遺傳因子，對 COPD 等慢性疾病提供長期保護。

這些研究為針灸應用於 ARDS、ALI、COPD 及缺血再灌注相關肺損傷提供了重要的 科學依據。