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c. Bromelain - Many studies have documented efficacy the antioxidant Nrf2 pathway and drives significant
of bromelain in reducing inflammation and anti-fibrotic activity benefit in both TGFβ treated cell
inflammatory diseases. Clinical benefit has been lines, and induced fibrosis in animal models.
371
shown in injuries, infections, respiratory tract Sulforaphane also upregulates GSH levels. 372,373
diseases, arthritis, inflammatory bowel disease, etc. It is noteworthy that curcumin, resveratrol,
Of particular importance here is its documented quercetin, and berberine have all been shown to
ability to decrease tissue edema and inflammation. promote AMPK. AMPK is a promoter of SIRT2, also
374
Several studies have shown that bromelain is known to inhibit NLRP3 inflammasome assembly.
23
effective in respiratory conditions such as asthma,
bronchitis, and sinusitis that are characterized by 5. Anti-Oxidant Support
increased mucus production and inflammation. Patient GSH status can be supported with oral GSH
Spirometry before and after bromelain treatment (liposomal forms appear to offer better absorption), NAC,
demonstrated increased FEV1 and vital capacity, vitamin E, and selenium. In addition, GSH can be delivered
which were suggested by the researchers to be a result by nebulizer or by IV. It may be appropriate to give both
of bromelain’s mucolytic activity. 352,353 NAC and GSH, in service of supporting GSH status.
Of particular interest here is the limited research When available, lab testing can support the clinician’s
showing that bromelain decreases cytokines. A monitoring of GSH levels.
placebo-controlled randomized clinical trial found that
high-dose oral bromelain showed immunomodulation NAC and GSH – Oral and Nebulized Delivery
of both Th1- and Th2- cytokines. Nebulized NAC and reduced GSH have a long history
354
of clinical use by natural/ integrative/ functional/ holistic
d. Resveratrol - Constituents of resveratrol have been doctors for the treatment of COPD and other chronic
shown to reduce inflammation via several mechanisms inflammatory lung conditions. While there is substantial
including downregulation of IL-6 and TNFα and research support for the value of oral NAC and oral GSH
promotion of Sirtuins. 355-358 Crucial to the utility of in respiratory illnesses, the research to date on the
resveratrol is its ability to inhibit the accumulation of nebulized delivery is limited but encouraging.
acetylated α-tubulin caused by mitochondrial damage NAC—oral, IV and nebulized—has considerable
in macrophages stimulated by NLRP3-inflammasome research support for improving respiratory tract
induction. Inflammasome assembly is strongly induced immunity, normalization of inflammation, helping
by acetylated α-tubulin. Resveratrol upregulates SIRT2, reduce excessive mucous secretion and functioning as a
a known deacetylator of α-tubulin. 359-361 The utility of mucolytic. A recent review well summarized its value in
resveratrol has been studied in SARS-CoV-1. respiratory diseases:
362
Resveratrol has been shown to protect lung epithelia
against the effects of cigarette smoke by upregulating Biological and pharmacological effects of NAC include
Nrf2 to promote GSH. improvement in rheological properties of mucus, reduction
363
The utility of resveratrol has been studied in a of excess mucin production, restoration of mucociliary
wide range of diseases including cardiovascular and clearance and production of sIgA, suppression of excess
364
production of IgE and IgG4, destruction of biofilms and
metabolic inflammatory processes. 365
inhibition of their formation, suppression of adhesion of
pathogenic bacteria to epithelial cells, antioxidant activity,
e. Quercetin - See the quercetin discussion above. regulation of the production of pro-inflammatory and
profibrotic cytokines. 375
f. Melatonin - See the melatonin discussion above.

g. Boswellia serrata (Boswellia) - Via a variety of While nebulized forms are likely more effective, oral NAC
mechanisms, boswellic acid (BA), an active constituent at 600 mg bid was shown in in a controlled study of
in Boswellia serrata, exerts a number of anti- patients with COPD to significantly improved PaO , PaCO ,
2
2
inflammatory effects. BA was shown to potently wheezing, and dyspnea and decrease the need for nasal
inhibit TGFβ induced pulmonary fibrosis and oxygen support. 376
5-lipoxygenase in an animal model. BA has also While most studies support this intervention, a clinical
366
been shown to significantly inhibit cyclooxygenase, study on mechanically ventilated patients showed that while
NFKB signaling and TNFα. 367,368 NAC was more effective than saline in decreasing mean
secretion density the results were not statistically significant
h. Sulforaphane - Sulforaphane is a well-studied (P = .087), likely due to a small sample size
anti-inflammatory phytochemical found in (20 patients in each arm). However, despite small sample
cruciferous vegetables that also inhibits NLRP3 size, NAC was significantly effective at increasing O
2
inflammasome biology. 369,370 Sulforaphane activates saturation. 377

24 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print Yanuck—Immuno-physiological Approach to COVID-19