lung injury

Dexmedetomidine hydrochloride (Precedex) is a potent, selective, orally active α2-adrenoceptor agonist with a Ki value of 1.08 nM. It shows 1620-fold selectivity over α1-adrenoceptors. Dexmedetomidine hydrochloride (Precedex) can protect against sepsis-induced acute lung injury through anti-inflammatory, anti-oxidative, and anti-apoptotic effects.

Sesamol (1,3-Benzodioxol-5-ol) could decrease lung inflammation and lipopolysaccharide (LPS)-induced lung injury in rats. Sesamol ameliorates inflammatory and oxidative damage by upregulating AMPK activation and Nrf2 signaling and blocking the NF-κB and MAPK signaling pathways and inhibits melanin biosynthesis by down-regulating tyrosinase activity and melanin production via regulation of gene expression of melanogenesis-related proteins through modulation of MITF activity, which promotes phosphorylation of p38 and JNK in melan-a cells.

Matrine (Vegard), an alkaloid isolated from the Sophora genus, acts as a kappa opioid receptor agonist.

Sivelestat (ONO5046) is a potent and selective inhibitor of neutrophil elastase with IC50 of 44 nM.

1. Linalool (Linalol), a natural compound of the essential oils, has been shown to have antinociceptive, antimicrobial, and anti-inflammatory properties. 2. Linalool was protected against LPS GalN-induced liver injury through induction of antioxidant defense via Nrf2 activating and reduction inflammatory response via NF-κB inhibition. 3. Linalool biosynthesis and accumulation might be involved in plant defense against bacterial and fungal pathogens and be associated with field resistance to citrus canker. 4. Linalool significantly increased the expression of antioxidant enzymes regulated by Nrf-2 and diminished lung tissue levels of several pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin (IL)-6.

Pemetrexed disodium (LY-231514) is a parenterally administered folate antagonist and antineoplastic agent, used in the treatment of non-small cell lung cancer and malignant mesothelioma. Pemetrexed disodium therapy has been associated with moderate rates of serum enzyme elevations during therapy, but has not been convincingly linked to instances of acute, clinically apparent liver injury.

Nrf2 activator-1 is a potent activator of NF-E2-related factor 2 (Nrf2) and can be used to study COPD and other respiratory diseases, including asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and pulmonary fibrosis.

Maresin 1 is a small molecule compound biosynthesized by macrophages (MΦ) with significant anti-inflammatory activity that attenuates LPS-induced lung injury in mice by inhibiting neutrophil adhesion and decreasing the levels of pro-inflammatory cytokines, and stimulates intracellular Ca2+ production and secretion.

GW274150 is an orally active, selective and potent dual inhibitor of NADPH-dependent human nitric oxide synthase (iNOS) (Kd=40 nM) and rat inducible nitric oxide synthase (iNOS).GW274150 has a low activity against endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) in humans and rats. GW274150 showed protective effects in an inflammatory model of acute lung injury.

N-Oleoyl valine is an endogenous N-acyl amine that acts as an antagonist at the transient receptor potential vanilloid type 3 (TRPV3) receptor, which is involved in thermoregulation. N-Oleoyl valine is increased in mice following cold exposure for up to at least 16 days. Acute lung injury in mice increases the concentration of N-Oleoyl valine in lung tissue. N-acyl amines also promote mitochondrial uncoupling.

1. Peiminine (Raddeanine) is an effective inhibitor for lung inflammation and pulmonary fibrosis in a rat model of bleomycin-induced lung injury.

Phillyrin (Forsythin) is a novel AMPK activator, has anti-obesity effects in nutritive obesity mice, it can prevent lipid accumulation in HepG2 cells by blocking the expression of SREBP-1c and FAS through LKB1 AMPK activation. Phillyrin(Forsythin) may be a new preventive agent of acute lung injury in the clinical setting, it potentially contributes to the suppression of the activation of MAPK and NF-κB pathways, it also has protective effects on H2O2-induced oxidative stress and apoptosis in PC12 cells.

Piceatannol (Astringenin) is an anti-inflammatory, immunomodulatory and antiproliferative agent. It inhibits p56lck and syk protein tyrosine kinases and inhibits NF-κB activation and gene expression of TNF-induced. It is synthetic from the conversion of resveratrol by cytochrome P450 1B1.

1. Peimisine (Ebeiensine) can affect M-receptor, excit β-receptor, restrain the release of internal calcium, and promote to releaseing nitrogen monoxidum in order to relax tracheal smooth muscle and relieve asthma. 2. Peimisine can attenuate lung tissue injury( ALI), LDH and MDA amount in ALI mice in a dose dependent manner, it also lower the total protein, total white blood cells, lymphocyte and neutrophilic leukocyte in bronchoalveolar lavage fluid( BALF); suggests that peimisine can play a protective role against LPS-induced acute lung injury. 3. Peimisine has the protective effect on the experimental hepatic fibrosis formation, the possible mechanisms are associated with inhibiting fibrogenesis and fibrosis accumulation, and decreasing lipid peroxidation. 4. Peimisine can inhibit angiotensin I converting enzyme activity in a dose-dependent manner, displaying 5 % inhibitory concentration values of 526.5 microM, thus, it may have antihypertensive action.

Manganese(salen) chloride (EUK-8) is a superoxide dismutase and catalase mimetic, serving as an antioxidant with oxyradical scavenging properties, and ameliorates acute lung injury in endotoxemic swine.

1. Praeruptorin C and E can relax swine coronary artery and decrease contractility in guinea-pig left atria, these effects are similar in many respects to those displayed by drugs that have calcium entry blocking activity. 2. Praeruptorin D and E can prot

L48H37 is a chemically stable analog of Curcumin. It exhibits potent inhibitory properties against myeloid differentiation protein 2 (MD2), acting as a specific inhibitor. Its mechanism involves inhibiting the interaction and signaling transduction of LPS-TLR4 MD2. L48H37 is primarily utilized in sepsis and lung injury research [1].

HCH6-1 is a competitive Formyl peptide receptor 1 (FPR1) antagonist.

Sivelestat sodium tetrahydrate (ONO5046 sodium tetrahydrate) is a competitive inhibitor of human neutrophil elastase, with an IC50 of 44 nM and a Ki of 200 nM. Sivelestat (EI546) sodium tetrahydrate has the potential for the study of acute lung injury acute respiratory distress syndrome or disseminated intravascular coagulation in COVID-19.

Ac2-26 acetate is an active N-terminal peptide of annexin A1(AnxA1). Ac2-26 acetate decreases AnxA1 protein expression and inhibits the activation of NF-κB and MAPK pathways in the injured lung tissue. Ac2-26 acetate attenuates ischemia-reperfusion-induced acute lung injury.

Ajoene is a disulfide that has been found inA. sativumand has diverse biological activities, including antibacterial, anticancer, antiplatelet, and antioxidant properties.1,2,3,4It is active against Gram-positive (MICs = 5-160 µg/ml) and Gram-negative bacteria (MICs = 136-200 µg/ml), as well as yeasts (MICs = 10-20 µg/ml).1Ajoene is cytotoxic to mouse melanoma cells (IC50= 18 µM), as well as human colon, lung, mammary, and pancreatic cancer cells (IC50s = 7-41 µM).2It reduces tumor growth in a B16/BL6 mouse model of melanoma when administered at a dose of 25 mg/kg every other day and decreases the number of lung metastases when administered prior to tumor cell inoculation at doses ranging from 1-25 mg/kg. It inhibits ADP- or collagen-induced platelet aggregation in isolated baboon platelets when used at concentrations ranging from 75 to 150 µg/ml and in platelet-rich plasma isolated from baboons when administered at a dose of 25 mg/kg.3Ajoene (25 mg/kg) prevents thrombus formation on damaged arterial walls in heparinized pigs in anin situmodel of thrombogenesis.5It also reduces high-fat diet-induced hepatic steatosis, histopathological markers of liver damage, thiobarbituric acid reactive substances (TBARS) formation, and protein oxidation in a mouse model of non-alcoholic fatty liver disease (NAFLD).4 1.Naganawa, R., Iwata, N., Ishikawa, K., et al.Inhibition of microbial growth by ajoene, a sulfur-containing compound derived from garlicAppl. Environ. Microbiol.62(11)4238-4242(1996) 2.Taylor, P., Noriega, R., Farah, C., et al.Ajoene inhibits both primary tumor growth and metastasis of B16/BL6 melanoma cells in C57BL/6 miceCancer Lett.239(2)298-304(2006) 3.Teranishi, K., Apitz-Castro, R., Robson, S.C., et al.Inhibition of baboon platelet aggregation in vitro and in vivo by the garlic derivative, ajoeneXenotransplantation10(4)374-379(2003) 4.Han, C.Y., Ki, S.H., Kim, Y.W., et al.Ajoene, a stable garlic by-product, inhibits high fat diet-induced hepatic steatosis and oxidative injury through LKB1-dependent AMPK activationAntioxid. Redox Signal.14(2)187-202(2011) 5.Apitz-Castro, R., Badimon, J.J., and Badimon, L.A garlic derivative, ajoene, inhibits platelet deposition on severely damaged vessel wall in an in vivo porcine experimental modelThromb. Res.75(3)243-249(1994)

1-Hydroxy-2,3,5-trimethoxyxanthone (HM-1) exhibits vasodilator action through an endothelium-dependent mechanism involving NO and an endothelium-independent mechanism by inhibiting Ca(2+) influx via L-type voltage-operated Ca(2+) channels. A minor contribution to HM-1's effects may stem from inhibiting protein kinase C-mediated release of intracellular Ca(2+) stores. At 1 µg mL, HM-1 effectively inhibits osteoclast differentiation in co-cultures with mouse osteoblastic calvarial and bone marrow cells and protects mice from acute lung injury induced by lipopolysaccharide (LPS), likely by increasing IκB-α protein expression and suppressing inducible nitric oxide synthase and cyclooxygenase-Ⅱ protein expression.

Piceatannol 3'-O-glucoside (Piceatannol 3-glycoside) increases pulmonary blood oxygen tension and decreases pulmonary interstitial edema, so it can protect lung injury.

6'-Sialyllactose Sodium Salt (6'-N-Acetylneuraminyl-D-lactose sodium salt), an oligosaccharide present in breast milk, is protective against LPS-induced ALI and attenuates LPS-induced lung injury by inhibiting the STAT1 and NF-κB signaling pathways. Diquat dibromide

Aviptadil Acetate (Vasoactive Intestinal Peptide acetate salt) induces pulmonary vasodilation and inhibits the proliferation of vascular SMCs and platelet aggregation. Avitadil acetate can be used for research on pulmonary fibrosis, pulmonary hypertension (PAH), and respiratory failure caused by SARS-CoV-2.

Nezulcitinib (TD-0903) is an inhaled, lung-selective pan-Janus kinase (JAK) inhibitor used to study COVID-19-associated acute lung injury and impaired oxygenation.

AZD1236 is a potent and reversible inhibitor of human MMP-9 and MMP-12 (IC50 = 4.5 and 6.1nM, respectively), with >10-fold selectivity to MMP-2 and MMP-13 and >350-fold selectivity to other members of the enzyme family. AZD1236 activity is approximately 20 to 50-fold lower at the rat, mouse, and guinea pig orthologues. In acute models of lung injury, AZD1236 inhibited the haemorrhage and inflammation induced by instillation of human MMP-12 into rat lungs by ~80% at 0.81mg/kg, and also abolished macrophage infiltration into BAL fluid induced by tobacco smoke inhalation in the mouse.

(±)9(10)-DiHOME, the diol derivative of (±)9(10)-EpOME—a cytochrome P450-derived epoxide of linoleic acid also known as leukotoxin—is formed through the action of soluble epoxide hydrolase (sEH) in neutrophils. It exhibits toxicity towards Sf21 cells expressing sEH as well as tolacZ-expressing control cells, differing from leukotoxin which only harms sEH-containing cells. Furthermore, combined exposure to 9(10)- and 12(13)-DiHOME leads to cell death in rabbit renal proximal tubule cells by disrupting mitochondrial respiration, and causes lung injury, respiratory distress, and mortality in mice, highlighting its role as a toxic lipid mediator. Specifically, 9(10)-DiHOME has been associated with acute respiratory distress syndrome (ARDS), a severe and often deadly complication in patients with major burns. Elevated levels of this compound have been detected in the bronchoalveolar lavage fluid (BALF) of women, but not men, with chronic obstructive pulmonary disease (COPD), and its levels are also increased in patients with allergic asthma, indicating its significance in respiratory conditions.

BRL 44408 Maleate is a potent α2A-adrenoceptor antagonist with antidepressant and analgesic activity that reduces lipopolysaccharide (LPS)-induced expression and attenuates endogenous lipopolysaccharide-induced acute lung injury through inhibition of the mitogen-activated protein kinase kinase extracellularly regulated protein kinase signaling pathway in mice.

Daxdilimab, an anti-ILT7 monoclonal antibody, targets the ILT7 cell surface molecule exclusive to pDC dendritic cells. It shows potential for treating acute lung injury (ALI) in COVID-19 infected patients, as indicated in research [1] [2].

Suvratoxumab (MEDI4893) is a high-affinity, long-acting humanized IgG1κ anti-α-toxin monoclonal antibody. It effectively neutralizes α-toxin, a principal virulence factor of S. aureus, enhancing survival and diminishing lung injury in an immunocompromised mouse model of pneumonia. Additionally, Suvratoxumab augments the antibacterial efficacy of Vancomycin and Linezolid [1] [2] [3].

Quin C1 is a selective and potent formylpeptide receptor 2 (FPR2/ALX) agonist with anti-inflammatory activity, inhibits neutrophil and lymphocyte production in BALF, and reduces the expression of TNF-α, IL-1β, KC, and TGF-β1.Quin C1 is used in the study of lung injury.

Vipoglanstat is a prostaglandin E synthase inhibitor and an anti-inflammatory. Vipoglanstat ameliorates leukocyte infiltration and lung injury resulting from both endotoxin-induced and sepsis-induced lung injury.

FTY720 (S)-Phosphate, an S1P receptor 1 (S1PR1) agonist, is utilized in research on acute inflammatory diseases, including acute lung injury.

ACT-660602 is an orally active chemokine receptor CXCR3 antagonist (IC50: 204 nM) that inhibits T cell migration and has demonstrated significant efficacy in an in vivo model of acute lung injury. It is useful for studying autoimmune diseases.

TREM-1 inhibitory peptide M3 acts as a ligand-dependent antagonist of TREM-1, capable of suppressing systemic and pulmonary pro-inflammatory cytokine and chemokine production, thereby mitigating acute lung injury [1].

Antileukinate is a synthetic hexapeptide with an acetylated amino terminus and an amidated carboxyl terminus that inhibits the binding of CXC chemokines to the chemokine receptor CXCR2. It inhibits IL-8 binding to neutrophils (Ki = 2.7-13 μM), prevents neutrophil chemotaxis and β-glucuronidase release, and blocks IL-8-induced skin edema in rabbits. At 53 mg/kg, antileukinate has been shown to protect mice against acute pancreatitis and associated lung injury.

PI3Kδ-IN-14 (Compound (S)-29), a selective PI3Kδ inhibitor with an IC50 of 0.8 nM and a Kd of 84.8 nM, targets the ATP-binding site within the kinase domain of PI3Kδ, exhibiting anti-inflammatory properties by impeding the PI3K AKT pathway and alleviating acute lung injury (ALI) [1].

Anti-inflammatory agent 50 (compound a1), a derivative of Fusidic acid, exerts its effects through inhibition of inflammatory mediators including NO, IL-6, and TNF-α. It mitigates acute lung injury by modulating these mediators and suppressing the MAPK, NF-κB, and NLRP3 inflammasome signaling pathways [1].

Antidesmone is one compound mainly isolated from Ajugade cumbers Thunb (Labiatae). Antidesmone prevents acute lung injury via regulating MAPK and NF-κB activities.

Sucrose octasulfate (SOS), a component of the gastrointestinal protectant sucralfate, is an alkaline aluminum-sucrose complex that inhibits peptic hydrolysis and raises gastric pH, protecting esophageal epithelium against acid injury. It can bind to exosite II of thrombin (KD = ~1.4 μM) and inhibit its catalytic activity (IC50 = 4.5 μM) and, as such, has been used as a surrogate for heparin. Furthermore, SOS has been shown to inhibit tumor growth in mouse melanoma and lung carcinoma models by preventing fibroblast growth factor 2 (FGF-2) binding to endothelial cells and also by removing any pre-bound FGF-2 from these cells (IC50 = ~2 μg/ml).

PNU-282987 (free base) is a potent agonist of α7 nicotinic acetylcholine receptor (nAChR) with an EC50 of 154 nM and a functional antagonist of the 5-HT3 receptor with an IC50 of 4541 nM. It can be used for central and peripheral nervous system studies[1].

NF-κB-IN-8 is a competitive antagonist of LPS for MD-2 binding, and it impedes the expression of inflammatory factors by engaging MD-2. Additionally, it inhibits ALP activity and is usable in inflammation research, including acute lung injury (ALI) [1].

Tylvalosin (Acetylisovaleryltylosin) is a broad-spectrum macrolide antibiotic with antibacterial and antiviral properties, effective against PRRSV infection. It induces apoptosis and possesses anti-inflammatory activity. Furthermore, Tylvalosin mitigates oxidative stress and acute lung injury through the suppression of NF-κB activation [1] [2].

Zofenoprilat, an angiotensin-converting enzyme (ACE; IC50 = 8 nM for rabbit lung enzyme) inhibitor and the active metabolite of the prodrug zofenopril, effectively counters angiotensin I- or bradykinin-induced contractions in isolated guinea pig ileum (EC50s = 3 and 1 nM, respectively). At a concentration of 10 nM, Zofenoprilat not only diminishes basal endothelin-1 secretion and nitric oxide (NO) production but also safeguards against TNF-α-stimulated increases in reactive oxygen species (ROS) and reductions in glutathione (GSH) levels within human umbilical vein endothelial cells (HUVECs). Furthermore, at 10 µM, it delivers protection to primary human cardiac microvascular endothelial cells from doxorubicin-induced toxicity and enhances hydrogen sulfide (H2S) production, along with the adhesion, migration, and proliferation of HUVECs. Additionally, Zofenoprilat (400 µM) mitigates end diastolic pressure and lactate dehydrogenase (LDH) release, demonstrating therapeutic potential in a Langendorff isolated perfused rat heart model of ischemia-reperfusion injury.

iNOs-IN-3 is an orally active nitric oxide synthase (iNOS) inhibitor with an IC50 value of 3.342 μM that exhibits anti-inflammatory effects and can be used to study LPS-induced acute lung injury (ALI).

1. Ruscogenin has anti-inflammatory activity, suppressed zymosan A-evoked peritoneal total leukocyte migration in mice in a dose-dependent manner, 2. Ruscogenin inhibited adhesion of leukocytes to a human umbilical vein endothelial cell line (ECV34) injured by tumor necrosis factor-alpha (TNF-alpha) in a concentration-dependent manner. 3. Ruscogenin significantly attenuate LPS-induced acute lung injury via inhibiting expressions of TF and iNOS and NF-kappa B p65 activation.

20-5,14-HEDGE, a 20-HETE analog, protects against lung ischemic reperfusion injury in rats [1].