L-Arginine from the laboratory to clinical practice

As a semi-essential amino acid in the human body, L-arginine is not only a key precursor for nitric oxide (NO) synthesis but also a core substrate for the urea cycle and polyamine synthesis. Its role in inflammatory responses exhibits a "bidirectional regulatory" characteristic—laboratory studies have clearly confirmed that it participates in inflammatory balance through the NO pathway, metabolite regulation, and immune cell function modulation. However, clinical applications require precise evaluation based on inflammation type and patients’ underlying conditions (e.g., liver and kidney function, metabolic status). The translational connection between laboratory research and clinical practice not only reflects the guiding significance of mechanistic studies but also highlights the complexity of clinical scenarios.

I. Laboratory Level: Core Mechanisms of L-Arginine Regulating Inflammatory Responses

Laboratory studies (cell experiments, animal models) have clearly revealed the multi-pathway role of L-arginine in inflammatory regulation, centered on "NO-mediated anti-inflammatory effects" and "pro-inflammatory risks caused by metabolic competition," with variations in the direction of action across different inflammatory models.

1. Anti-Inflammatory Effects: NO-Centered Immune Regulation and Tissue Protection

NO, generated from L-arginine under the catalysis of nitric oxide synthase (NOS), is the key molecule for its anti-inflammatory effects. In immune-related cells such as macrophages and endothelial cells, low concentrations of NO inhibit inflammatory amplification through multiple mechanisms:

On one hand, NO suppresses the activation of nuclear factor κB (NF-κB)—a core transcription factor regulating the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). By modifying NF-κB subunits or interfering with its signaling pathways, NO reduces the release of pro-inflammatory factors.

On the other hand, NO stabilizes the vascular endothelial barrier, decreases capillary permeability, and reduces the migration and infiltration of inflammatory cells (e.g., neutrophils) into tissue interstitium, alleviating local edema and tissue damage. This effect has been verified in animal models of acute lung injury and ischemia-reperfusion inflammation—supplementation with L-arginine significantly reduces the infiltration of neutrophils in the lung tissue of model animals while increasing the expression level of the anti-inflammatory factor IL-10.

In addition, metabolites of L-arginine (e.g., ornithine, polyamines) also participate in anti-inflammatory regulation:

Ornithine accelerates the repair of damaged tissues by promoting collagen synthesis, indirectly alleviating post-inflammatory tissue damage.

Polyamines stabilize intracellular lysosomal membranes, reducing the damage to surrounding cells caused by lysosomal enzyme release. In intestinal mucosal inflammation models, supplementation with L-arginine increases polyamine levels in intestinal tissues, enhances the integrity of the mucosal barrier, and reduces systemic inflammatory responses triggered by the translocation of intestinal bacterial endotoxins into the bloodstream.

2. Pro-Inflammatory Risks: Effects of NOS Subtype Competition and Metabolic Imbalance

Laboratory studies have also found that under specific inflammatory conditions (e.g., severe infection, post-trauma), L-arginine may indirectly promote inflammation through "metabolic shunting":

Inducible nitric oxide synthase (iNOS) in the body is highly activated. iNOS has low affinity for L-arginine and requires high concentrations of substrate to continuously catalyze NO synthesis. Excessive NO combines with superoxide anions to form peroxynitrite (ONOO⁻), a highly oxidizing substance that damages intracellular proteins, lipids, and DNA, exacerbating tissue inflammation and cell apoptosis.

Meanwhile, the massive activation of iNOS competes for substrates with other arginine-dependent enzymes (e.g., arginase), reducing the production of ornithine catalyzed by arginase. This impairs tissue repair and instead prolongs inflammation.

Furthermore, in animal models of L-arginine deficiency (e.g., liver cirrhosis, chronic kidney disease models), excessive supplementation of L-arginine may disrupt the balance of amino acid metabolism in the body:

On one hand, excess arginine may be decomposed by intestinal bacteria to produce harmful substances such as putrescine, which irritate the intestinal mucosa and trigger local inflammation.

On the other hand, when liver and kidney function is impaired, the metabolic clearance capacity of arginine decreases. The accumulation of excess substrate may indirectly activate the pro-inflammatory signaling pathways of immune cells, leading to increased release of pro-inflammatory factors.

II. Clinical Level: Applications and Controversies of L-Arginine in Inflammation-Related Diseases

Based on laboratory mechanisms, numerous studies have been conducted on the clinical application of L-arginine in inflammation-related diseases. However, its efficacy varies significantly depending on disease type, patient population, and administration method (dose, course of treatment), and no unified clinical recommendation standards have been established. The focus is mainly on two scenarios: "acute inflammation" and "chronic inflammation."

1. Acute Inflammatory Diseases: From "Adjuvant Improvement" to "Cautious Use"

In acute hypermetabolic inflammatory diseases such as acute pancreatitis, severe burns, and sepsis, patients often experience L-arginine deficiency due to insufficient intake and increased consumption. At this point, L-arginine supplementation is considered to help alleviate inflammation by improving microcirculation and regulating immune function:

In clinical studies on patients with acute pancreatitis, supplementation of L-arginine (10–15 g per day) via enteral nutrition significantly reduces serum TNF-α and IL-6 levels in patients, improves intestinal mucosal blood flow, reduces bacterial translocation caused by intestinal barrier damage, and shortens hospital stay.

In patients with severe burns, supplementation with L-arginine improves local microcirculation at the wound site, promotes fibroblast proliferation, accelerates wound healing, and indirectly alleviates local inflammatory responses at the wound.

However, the application of L-arginine in diseases characterized by "excessive inflammatory responses" (e.g., sepsis) is controversial:

Some clinical studies have shown that iNOS is already highly activated in sepsis patients. Supplementation with L-arginine may increase ONOO⁻ production, exacerbate multi-organ damage, and even increase patient mortality.

Therefore, current clinical guidelines mostly recommend that for sepsis patients, the body’s NO metabolic status (e.g., detecting serum nitrate/nitrite levels) should be evaluated first. Only when L-arginine deficiency is confirmed and iNOS activity is not excessively elevated should cautious low-dose supplementation (5–8 g per day) be administered to avoid blind use.

2. Chronic Inflammatory Diseases: From "Mechanistic Potential" to "Clinical Limitations"

In chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease (IBD), and chronic obstructive pulmonary disease (COPD), laboratory studies suggest that L-arginine may alleviate chronic inflammatory damage by regulating immune cell function (e.g., inhibiting Th17 cell differentiation, promoting Treg cell proliferation). However, there is no consensus on the effect of clinical translation.

Taking inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as an example:

In animal models, L-arginine supplementation improves mucosal blood flow by increasing intestinal NO levels, reduces the secretion of pro-inflammatory factors, and alleviates intestinal mucosal inflammation.

However, in clinical studies, results vary significantly across different cohorts: Some small-scale studies show that mild ulcerative colitis patients supplementing with L-arginine (8–12 g per day) experience reduced levels of fecal calprotectin (an intestinal inflammation marker) and improved symptoms. However, large-scale multi-center studies find no significant difference in symptom remission rates between IBD patients with moderate to severe disease supplemented with L-arginine and those in the placebo group. Additionally, some patients experience adverse reactions such as abdominal distension and diarrhea due to intestinal malabsorption, which is presumably related to intestinal flora disorders and abnormal arginine metabolic pathways in patients.

The clinical application of L-arginine in rheumatoid arthritis also faces challenges:

Patients with rheumatoid arthritis have abnormal local NO metabolism in joints. Supplementation with L-arginine may affect both anti-inflammatory and pro-inflammatory pathways. Some studies show that its effect on improving joint pain and swelling is limited, and long-term use may increase the burden on liver and kidney function. Therefore, it is currently only used as "adjuvant nutritional support" rather than a primary treatment.

III. Translational Challenges and Future Directions from Laboratory to Clinic

Although extensive laboratory evidence has been obtained regarding the role of L-arginine in inflammatory responses, there remains a "disconnection between mechanism and efficacy" in clinical applications. The core challenges focus on the following three aspects:

Individual Metabolic Differences: Different patients (e.g., with varying liver and kidney function, age, and underlying diseases) have different metabolic capacities for L-arginine, leading to variations in in vivo NO production and metabolite distribution at the same dose. This makes it difficult to establish unified clinical dose standards.

Complexity of Inflammation Types: The pathogenesis of acute inflammation (e.g., infectious inflammation, traumatic inflammation) differs from that of chronic inflammation (e.g., autoimmune inflammation). The activity of L-arginine’s target molecules (e.g., iNOS, arginase) varies, requiring targeted design of clinical protocols.

Lack of Precise Monitoring Tools: Currently, there is a lack of convenient clinical indicators (e.g., real-time NO concentration, arginine metabolic enzyme activity) to evaluate the in vivo action status of L-arginine, making it difficult to dynamically adjust administration regimens and increasing the blindness of clinical application.

Future translational research should focus on "precision" and "individualization":

On one hand, molecular biology technologies (e.g., genetic testing, metabolomics) can be used to screen patients with inflammation subtypes sensitive to L-arginine and identify suitable populations.

On the other hand, targeted delivery systems (e.g., intestinal mucosa-targeted preparations, inflammation site-responsive carriers) can be developed to enable L-arginine release at specific inflammatory sites, reducing side effects caused by systemic metabolism.

Meanwhile, real-time monitoring technologies (e.g., portable NO detectors) can be integrated to dynamically adjust doses, achieving a clinical application model of "clear mechanism, precise dosage, and population adaptation," and promoting L-arginine from laboratory mechanistic research to more effective clinical inflammation management.