Category Archives: Pulmonary Fibrosis

Alcohol Activates Cannabinoid Receptor 1 and 2 in a Model of Pathogen Induced Pulmonary Inflammation

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“Alcohol use disorder (AUD) is defined as patterns of alcohol misuse and affects over 30 million people in the US. AUD is a systemic disease with the epidemiology of acute lung injury and excessive alcohol use established in the literature. However, the distinct mechanisms by which alcohol induces the risk of pulmonary inflammation are less clear.

A compelling body of evidence shows that cannabinoid receptors (CB1R and CB2R) play a relevant role in AUD. For this study, we investigated the role of CBR signaling in pulmonary immune activation.

Using a human macrophage cell line, we evaluated the expression of CBR1 and CBR2 after cells were exposed to EtOH, +/- cannabinoid agonists and antagonists by flow cytometry. We also evaluated the expression of cannabinoid receptors from the lungs of adolescent mice exposed to acute binge EtOH +/- cannabinoid agonists and antagonists at both resting state and after microbial challenge via western blot, rt-PCR, cytokine analysis, and histology.

Our results suggest that EtOH exposure modulates the expression of CBR1 and CBR2. Second, EtOH may contribute to the release of DAMPs and other proinflammatory cytokines, Finally, microbial challenge induces pulmonary inflammation in acute binge EtOH-exposed mice, and this observed immune activation may be CBR-dependent.

We have shown that adolescent binge drinking primes the lung to subsequent microbial infection in adulthood and this response can be mitigated with cannabinoid antagonists. These novel findings may provide a framework for developing potential novel therapeutics in AUD research.”

https://pubmed.ncbi.nlm.nih.gov/39251147/

  • “Acute binge alcohol modulates the levels of cannabinoid receptor expression in the lung.
  • •Microbial challenge induces pulmonary inflammation in mice previously exposed to binge alcohol
  • •Excessive alcohol paired with microbial challenge contributes to the release of proinflammatory cytokines in the lung
  • •Cannabinoid receptor antagonists block alcohol-induced pulmonary inflammation”

https://www.sciencedirect.com/science/article/abs/pii/S0378427424010981?via%3Dihub


Cannabidiol suppresses silica-induced pulmonary inflammation and fibrosis through regulating NLRP3/TGF-β1/Smad2/3 pathway

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“Silica-induced pulmonary fibrosis is an irreversible and progressive lung disease with limited treatments available. In this work, FDA-approved cannabidiol (CBD) was studied for its potential medical use in silicosis.

In silicosis female C57BL/6 mice model, oral CBD or pirfenidone (PFD) on day 1 after intratracheal drip silica (150 mg/mL) and continued for 42 days. Lung inflammatory and fibrotic changes were studied using ELISA kits, H&E staining and Masson staining. Osteopontion (OPN) and α-smooth muscle actin (α-SMA) expression in lung tissues was determined using immunohistochemical staining.

The results indicated that CBD attenuated silica-induced pulmonary inflammation and fibrosis.

Human myeloid leukemia mononuclear cells (THP-1) were treated with silica (200 μg/mL) to induce cell damage, then CBD (10 μM, 20 μM) and PFD (100 μM) were incubated. In vitro experiments showed that CBD can effectively reduce the expression of NLRP3 inflammasome in THP-1 cells and subsequently block silica-stimulated transformation of fibromuscular-myofibroblast transition (FMT) by culturing human embryonic lung fibroblasts (MRC-5) in conditioned medium of THP-1 cells.

Therefore, CBD exhibited the potential therapy for silicosis through inhibiting the silica-induced pulmonary inflammation and fibrosis via the NLRP3/TGF-β1/Smad2/3 signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/39244899/

“CBD ameliorates silica-induced pulmonary inflammation and fibrosis.”

https://www.sciencedirect.com/science/article/abs/pii/S1567576924016096?via%3Dihub

“Silica compounds are found throughout the environment in rocks, sand, clay, soil, air, and water. Silica is used in many commercial products, such as bricks, glass and ceramics, plaster, granite, concrete, cleansers, skin care products, and talcum powder. Some forms of amorphous silica are used as food additives, food wrappings, toothpaste and cosmetics. The general population is exposed to silica through air, certain types of indoor dust (such as from concrete), food, water, soil, and some consumer products. The exposure of greatest concern is through air.”

https://wwwn.cdc.gov/TSP/ToxFAQs/ToxFAQsDetails.aspx?faqid=1492&toxid=290#:~:text=Silica%20is%20used%20in%20many,food%20wrappings%2C%20toothpaste%20and%20cosmetics.

CB2R agonist prevents nicotine induced lung fibrosis.

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 Publication Cover“Nicotine stimulates fibroblast proliferation while increasing inflammation and fibrosis of tissues.

The cannabinoid receptor 1 (CB1R) is mainly located in the CNS, while cannabinoid receptor 2 (CB2R) is located in the immune cells within the body. CB2R regulates inflammatory processes and fibroblast function.

Nicotine induces interstitial lung fibrosis that is enhanced by the CB2R antagonist and diminished by the CB2R agonist. Therefore, the CB2R agonist may offer a protection against fibrosis.”

https://www.ncbi.nlm.nih.gov/pubmed/30675824

https://www.tandfonline.com/doi/abs/10.1080/01902148.2018.1543368?journalCode=ielu20

Activation of cannabinoid receptor type 2 by JWH133 alleviates bleomycin-induced pulmonary fibrosis in mice.

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“Activation of cannabinoid receptor type 2 has been shown to have anti-fibrosis function in skin and heart.

In this research, we aimed to investigate the role of cannabinoid receptor type 2 in pulmonary fibrosis in vitro and in vivo.

Our research indicated that activating cannabinoid receptor type 2 by a pharmacological method might be a potential strategy for pulmonary fibrosis.”  https://www.ncbi.nlm.nih.gov/pubmed/29262578

“In conclusion, we demonstrate that activating cannabinoid receptor type 2 by selective agonist JWH133 is a potential strategy for pulmonary fibrosis. Our researches offer a new choice for this life-threatening disease.” http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=21975&path[]=69664

Two FDA drug approvals for idiopathic pulmonary fibrosis (IPF)

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“Pulmonary fibrosis is a disease in which tissue deep inside the lungs becomes thick, stiff, and scarred, decreasing the lungs’ ability to expand to take in air, and making it difficult to breathe. This is a progressive disease in which scarring and lack of elasticity in the lungs continues to increase until the patient can no longer breathe enough to sustain life.

Until recently, patients in the U.S. suffering from idiopathic pulmonary fibrosis (IPF), a form of pulmonary fibrosis in which the cause is unknown, had no drug treatment  approved by FDA for this debilitating, incurable, and terminal condition. However, this month, FDA approved Ofev (nintedanib) and Esbriet (pirfenidone), two important new therapies for the treatment of patients with IPF. Both drugs are “first-in-class” products that offer new hope for patients in the U.S. with IPF.

Researchers don’t understand exactly how Ofev and Esbriet work in the body against IPF, but the drugs seem to inhibit important pathways that help to prevent scarring. Neither drug is a cure. IPF may still progress after patients use these drugs. However, each drug has been shown to significantly slow the progression of the disease.”  https://blogs.fda.gov/fdavoice/index.php/2014/10/two-fda-drug-approvals-for-idiopathic-pulmonary-fibrosis-ipf/

Two FDA drug approvals for idiopathic pulmonary fibrosis (IPF)

http://www.thctotalhealthcare.com/category/pulmonary-fibrosis/

Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica.

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“We explored the role of interleukin 1 (IL-1) in two models of pulmonary fibrosis (PF), elicited in mice by the intra-tracheal instillation of bleomycin or silica

This study indicates that IL-1ra might be useful for the treatment of incipient or established pulmonary fibrosis.”

https://www.ncbi.nlm.nih.gov/pubmed/7683505

http://www.sciencedirect.com/science/article/pii/104346669390024Y?via%3Dihub

“Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. Cannabinoids (CBs) also exert potent anti-inflammatory and neuroprotective effects.  We report for the first time that both CB1 and CB2 receptors modulate release of endogenous IL-1ra. Endogenous IL-1ra is essential for the neuro-protective effects of CBs against excessive activation of glutamate receptors (excitotoxicity). These data suggest a novel neuroprotective mechanism of action for CBs in response to inflammatory or excitotoxic insults that is mediated by both CB1 and CB2 receptor-dependent pathways.”  https://www.ncbi.nlm.nih.gov/pubmed/12878687

Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis.

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“Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease without effective treatment, highlighting the need for identifying new targets and treatment modalities. The pathogenesis of IPF is complex, and engaging multiple targets simultaneously might improve therapeutic efficacy.

To assess the role of the endocannabinoid/cannabinoid receptor 1 (endocannabinoid/CB1R) system in IPF and its interaction with inducible nitric oxide synthase (iNOS) as dual therapeutic targets, we analyzed lung fibrosis and the status of the endocannabinoid/CB1R system and iNOS in mice with bleomycin-induced pulmonary fibrosis (PF) and in lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF, as well as controls. In addition, we investigated the antifibrotic efficacy in the mouse PF model of an orally bioavailable and peripherally restricted CB1R/iNOS hybrid inhibitor.

We report that increased activity of the endocannabinoid/CB1R system parallels disease progression in the lungs of patients with idiopathic PF and in mice with bleomycin-induced PF and is associated with increased tissue levels of interferon regulatory factor-5. Furthermore, we demonstrate that simultaneous engagement of the secondary target iNOS by the hybrid CB1R/iNOS inhibitor has greater antifibrotic efficacy than inhibition of CB1R alone. This hybrid antagonist also arrests the progression of established fibrosis in mice, thus making it a viable candidate for future translational studies in IPF.”  https://www.ncbi.nlm.nih.gov/pubmed/28422760

 “The limited success of medications with a single target suggests that multitargeted therapies may be more effective, considering the multifactorial pathology of IPF. Here, we report that a dual-target hybrid inhibitor of peripheral CB1R and iNOS completely arrested the progression of BL-PF and dramatically improved the survival rate in a progression arrest treatment paradigm, providing proof of principle for a polypharmacology approach in this preclinical model of IPF. “
 https://insight.jci.org/articles/view/92281

“Our results show that CB1 signaling plays a key pathological role in the development of radiation-induced pulmonary inflammation and fibrosis, and peripherally restricted CB1 antagonists may represent a novel therapeutic approach against this devastating complication of radiotherapy/irradiation. In summary, we provide the first evidence on the key pathological role of CB1 signaling in radiation-induced pulmonary fibrogenesis and show that peripherally restricted CB1 antagonists may represent a novel therapeutic approach against this devastating and untreatable complication of radiotherapy/irradiation. Our results also suggest that targeting CB1 may provide benefits in other lung diseases associated with inflammation and fibrosis.”  http://www.atsjournals.org/doi/10.1165/rcmb.2014-0331OC

“Pure Δ9-tetrahydrocannabivarin and a Cannabis sativa extract with high content in Δ9-tetrahydrocannabivarin inhibit nitrite production in murine peritoneal macrophages. THCV down-regulated the over-expression of inducible nitric oxide synthase (iNOS). THCV counteracted LPS-induced up-regulation of CB1 receptors.  Cannabis use has immunomodulatory and anti-inflammatory effects.”  http://www.ncbi.nlm.nih.gov/pubmed/27498155

 “As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances. Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents.”  https://www.ncbi.nlm.nih.gov/pubmed/27435265

Pure Δ9-tetrahydrocannabivarin and a Cannabis sativa extract with high content in Δ9-tetrahydrocannabivarin inhibit nitrite production in murine peritoneal macrophages.

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“Historical and scientific evidence suggests that Cannabis use has immunomodulatory and anti-inflammatory effects.

We have here investigated the effect of the non-psychotropic phytocannabinoid Δ9-tetrahydrocannabivarin (THCV) and of a Cannabis sativa extract with high (64.8%) content in THCV (THCV-BDS) on nitric oxide (NO) production, and on cannabinoid and transient receptor potential (TRP) channel expression in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages.

THCV-BDS and THCV exhibited similar affinity in radioligand binding assays for CB1 and CB2 receptors, and inhibited, via CB2 but not CB1 cannabinoid receptors, nitrite production evoked by LPS in peritoneal macrophages.

THCV down-regulated the over-expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin 1β (IL-1β) proteins induced by LPS.

Furthermore, THCV counteracted LPS-induced up-regulation of CB1 receptors, without affecting the changes in CB2, TRPV2 or TRPV4 mRNA expression caused by LPS. Other TRP channels, namely, TRPA1, TRPV1, TRPV3 and TRPM8 were poorly expressed or undetectable in both unstimulated and LPS-challenged macrophages.

It is concluded that THCV – via CB2 receptor activation – inhibits nitrite production in macrophages. The effect of this phytocannabinoid was associated with a down-regulation of CB1, but not CB2 or TRP channel mRNA expression.”

http://www.ncbi.nlm.nih.gov/pubmed/27498155

Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis

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“Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment.

Endocannabinoids acting via cannabinoid-1 receptors (CB1R) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CB1R antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects.

Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases.

Here, we introduce a peripherally restricted, orally bioavailable CB1R antagonist, which accumulates in liver to release an iNOS inhibitory leaving group.

Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CB1R/iNOS antagonists have therapeutic potential in liver fibrosis.

Regarding the pharmacodynamics of the hybrid CB1R/iNOS inhibitor, two important principles have emerged from efforts to develop effective antifibrotic therapies. First, antifibrotic treatment strategies could aim to control the primary disease, to inhibit fibrogenic gene expression and signaling, to promote molecular mechanisms involved in fibrosis regression, or a combination of these. Second, with multiple molecular mechanisms and signaling pathways involved in fibrosis, targeting more than one could increase antifibrotic efficacy, and the hybrid CB1R/iNOS inhibitor embodies optimal characteristics on both accounts.

As to the first principle, both the endocannabinoid/CB1R system and iNOS are ideal targets, as they are known to be involved directly in the fibrotic process and also in the conditions predisposing to liver fibrosis, as detailed in the Introduction. An emerging major predisposing factor to liver fibrosis is nonalcoholic fatty liver disease, and CB1R blockade has proven effective in mitigating obesity-related hepatic steatosis in both rodent models and humans. The other two major predisposing factors, alcoholic fatty liver disease and viral hepatitis, also involve increased CB1R activity. Hepatic CB1R expression is induced either by chronic ethanol intake or the hepatitis C virus, and CB1R blockade mitigates alcohol-induced steatosis and inhibits hepatitis C virus production.

The dual targeting of peripheral CB1R and iNOS demonstrated here exemplifies the therapeutic gain obtained by simultaneously hitting more than one molecule, which could then engage distinct as well as convergent cellular pathways. The advantage of such an approach is highlighted by emerging experience with recently developed antifibrotic medications, which indicates that targeting a single pathway has limited effect on fibrotic diseases.

Thus, the approach illustrated by the present study has promise as an effective antifibrotic strategy.”

http://insight.jci.org/articles/view/87336

Cannabinoids, inflammation, and fibrosis.

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“Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs).

As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis.

A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented.

Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations-Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)-that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (CT-3, AJA; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals.

The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances.

Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.”

http://www.ncbi.nlm.nih.gov/pubmed/27435265