Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release.

Immune cell chemotaxis to the sites of pathogen invasion is critical for fighting infection, but in life-threatening conditions such as sepsis and Covid-19, excess activation of the innate immune system is thought to cause a damaging invasion of immune cells into tissues and a consequent excessive release of cytokines, chemokines and neutrophil extracellular traps (NETs). In these circumstances, tempering excessive activation of the innate immune system may, paradoxically, promote recovery. Here we identify the antimalarial compound artemisinin as a potent and selective inhibitor of neutrophil and macrophage chemotaxis induced by a range of chemotactic agents. Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. Inhibition of SERCA3 by artemisinin was irreversible and was inhibited by iron chelation, suggesting iron-catalysed alkylation of a specific cysteine residue in SERCA3 as the mechanism by which artemisinin inhibits neutrophil motility. In murine infection models, artemisinin potently suppressed neutrophil invasion into both peritoneum and lung in vivo and inhibited the release of cytokines/chemokines and NETs. This work suggests that artemisinin may have value as a therapy in conditions such as sepsis and Covid-19 in which over-activation of the innate immune system causes tissue injury that can lead to death.

Xuanfei Baidu Decoction reduces acute lung injury by regulating infiltration of neutrophils and macrophages via PD-1/IL17A pathway.

The pathogenic hyper-inflammatory response has been revealed as the major cause of the severity and death of the Corona Virus Disease 2019 (COVID-19). Xuanfei Baidu Decoction (XFBD) as one of the "three medicines and three prescriptions" for the clinically effective treatment of COVID-19 in China, shows unique advantages in the control of symptomatic transition from moderate to severe disease states. However, the roles of XFBD to against hyper-inflammatory response and its mechanism remain unclear. Here, we established acute lung injury (ALI) model induced by lipopolysaccharide (LPS), presenting a hyperinflammatory process to explore the pharmacodynamic effect and molecular mechanism of XFBD on ALI. The in vitro experiments demonstrated that XFBD inhibited the secretion of IL-6 and TNF-α and iNOS activity in LPS-stimulated RAW264.7 macrophages. In vivo, we confirmed that XFBD improved pulmonary injury via down-regulating the expression of proinflammatory cytokines such as IL-6, TNF-α and IL1-ß as well as macrophages and neutrophils infiltration in LPS-induced ALI mice. Mechanically, we revealed that XFBD treated LPS-induced acute lung injury through PD-1/IL17A pathway which regulates the infiltration of neutrophils and macrophages. Additionally, one major compound from XFBD, i.e. glycyrrhizic acid, shows a high binding affinity with IL17A. In conclusion, we demonstrated the therapeutic effects of XFBD, which provides the immune foundations of XFBD and fatherly support its clinical applications.

New C9 -Monoterpenoid Alkaloids Featuring a Rare Skeleton with Anti-Inflammatory and Antiviral Activities from Forsythia suspensa.

Forsyqinlingines C (1) and D (2), two C9 -monoterpenoid alkaloids bearing a rare skeleton, were isolated from the ripe fruits of Forsythia suspensa. Their structures, including absolute configurations, were fully elucidated by extensive spectroscopic data and ECD experiments. The plausible biogenetic pathway for compounds 1 and 2 was also proposed. In vitro, two C9 -monoterpenoid alkaloids showed anti-inflammatory activity performed by the inhibitory effect on the release of ß-glucuronidase in rat polymorphonuclear leukocytes (PMNs), as well as antiviral activity against influenza A (H1N1) virus and respiratory syncytial virus (RSV).

Evaluation of Berberine as an Adjunct to TB Treatment.

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.

Neutrophil-Dependent Immunity During Pulmonary Infections and Inflammations.

Rapid recruitment of neutrophils to an inflamed site is one of the hallmarks of an effective host defense mechanism. The main pathway through which this happens is by the innate immune response. Neutrophils, which play an important part in innate immune defense, migrate into lungs through the modulation actions of chemokines to execute a variety of pro-inflammatory functions. Despite the importance of chemokines in host immunity, little has been discussed on their roles in host immunity. A holistic understanding of neutrophil recruitment, pattern recognition pathways, the roles of chemokines and the pathophysiological roles of neutrophils in host immunity may allow for new approaches in the treatment of infectious and inflammatory disease of the lung. Herein, this review aims at highlighting some of the developments in lung neutrophil-immunity by focusing on the functions and roles of CXC/CC chemokines and pattern recognition receptors in neutrophil immunity during pulmonary inflammations. The pathophysiological roles of neutrophils in COVID-19 and thromboembolism have also been summarized. We finally summarized various neutrophil biomarkers that can be utilized as prognostic molecules in pulmonary inflammations and discussed various neutrophil-targeted therapies for neutrophil-driven pulmonary inflammatory diseases.

Targeting DCs for Tolerance Induction: Don't Lose Sight of the Neutrophils.

Chronic inflammatory disorders (CID), such as autoimmune diseases, are characterized by overactivation of the immune system and loss of immune tolerance. T helper 17 (Th17) cells are strongly associated with the pathogenesis of multiple CID, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. In line with the increasingly recognized contribution of innate immune cells to the modulation of dendritic cell (DC) function and DC-driven adaptive immune responses, we recently showed that neutrophils are required for DC-driven Th17 cell differentiation from human naive T cells. Consequently, recruitment of neutrophils to inflamed tissues and lymph nodes likely creates a highly inflammatory loop through the induction of Th17 cells that should be intercepted to attenuate disease progression. Tolerogenic therapy via DCs, the central orchestrators of the adaptive immune response, is a promising strategy for the treatment of CID. Tolerogenic DCs could restore immune tolerance by driving the development of regulatory T cells (Tregs) in the periphery. In this review, we discuss the effects of the tolerogenic adjuvants vitamin D3 (VD3), corticosteroids (CS), and retinoic acid (RA) on both DCs and neutrophils and their potential interplay. We briefly summarize how neutrophils shape DC-driven T-cell development in general. We propose that, for optimization of tolerogenic DC therapy for the treatment of CID, both DCs for tolerance induction and the neutrophil inflammatory loop should be targeted while preserving the potential Treg-enhancing effects of neutrophils.

Divergent impacts of tocilizumab and colchicine in COVID-19-associated coagulopathy: the role of alpha-defensins.

Patients who are severely affected by coronavirus disease 2019 (COVID-19) may develop a delayed onset 'cytokine storm', which includes an increase in interleukin-6 (IL-6). This may be followed by a pro-thrombotic state and increased D-dimers. It was anticipated that tocilizumab (TCZ), an anti-IL-6 receptor monoclonal antibody, would mitigate inflammation and coagulation in patients with COVID-19. However, clinical trials with TCZ have recorded an increase in D-dimer levels. In contrast to TCZ, colchicine reduced D-dimer levels in patients with COVID-19. To understand how the two anti-inflammatory agents have diverse effects on D-dimer levels, we present data from two clinical trials that we performed. In the first trial, TCZ was administered (8 mg/kg) to patients who had a positive polymerase chain reaction test for COVID-19. In the second trial, colchicine was given (0·5 mg twice a day). We found that TCZ significantly increased IL-6, α-Defensin (α-Def), a pro-thrombotic peptide, and D-dimers. In contrast, treatment with colchicine reduced α-Def and Di-dimer levels. In vitro studies show that IL-6 stimulated the release of α-Def from human neutrophils but in contrast to colchicine, TCZ did not inhibit the stimulatory effect of IL-6; raising the possibility that the increase in IL-6 in patients with COVID-19 treated with TCZ triggers the release of α-Def, which promotes pro-thrombotic events reflected in an increase in D-dimer levels.

Can immunological manipulation defeat SARS-CoV-2? Why G-CSF induced neutrophil expansion is worth a clinical trial: G-CSF treatment against COVID-19.

Immunity against SARS-CoV-2 that is acquired by convalescent COVID-19 patients is examined in reference to (A) the Th17 cell generation system in psoriatic epidermis and (B) a recently discovered phenomenon in which Th17 cells are converted into tissue-resident memory T (TRM ) cells with Th1 phenotype. Neutrophils that are attracted to the site of infection secrete IL-17A, which stimulates lung epithelial cells to express CCL20. Natural Th17 (nTh17) cells are recruited to the infection site by CCL20 and expand in the presence of IL-23. These nTh17 cells are converted to TRM cells upon encounter with SARS-CoV-2 and continue to exist as ex-Th17 cells, which exert Th1-like immunity during a memory response. G-CSF can induce nTh17 cell accumulation at the infection site because it promotes neutrophil egress from the bone marrow. Hence, G-CSF may be effective against COVID-19. Administration of G-CSF to patients infected with SARS-CoV-2 is worth a clinical trial.

Viral mimetic poly(I:C) induces neutrophil extracellular traps via PAD4 to promote inflammation and thrombosis.

Neutrophil extracellular traps (NETs) are extracellular webs of DNA, histones and granular contents that are released by neutrophils to control infections. However, NETs that is not properly regulated can propagate inflammation and thrombosis. It was recognized that viruses can induce NETs. As a synthetic analog of viral double-stranded (ds) RNA, polyinosinic-polycytidylic acid [poly(I:C)] is known to induce inflammation and thrombosis. However, whether and how poly(I:C) modulates NETs remains unclear. Here, we have demonstrated that poly(I:C) induced extracellular DNA traps in human neutrophils in a dose-dependent manner. Further, poly(I:C) or dsRNA virus elevated the levels of myeloperoxidase-DNA complexes and citrullinated histone H3, which are specific markers of NETs, in both neutrophil supernatants and mouse plasma. Interestingly, a potent peptidylarginine deiminase 4 (PAD4) inhibitor, BB-CL-Amidine (BB-CLA) or PAD4 knockdown effectively prevented poly(I:C)-induced NETs formation and release. In addition, BB-CLA abrogated poly(I:C)-triggered neutrophil activation and infiltration, and vascular permeability in lungs. BB-CLA also attenuated poly(I:C)-induced thrombocytopenia in circulation, fibrin deposition and thrombus formation in tissues. Taken together, these results suggest that viral mimetic poly(I:C) may induce NETs-dependent inflammation and thrombosis through PAD4, and that inhibiting PAD4 may become a good strategy to protect against viral infection-caused inflammation/thrombosis-related pathological conditions of diseases.

Lack of detectable short-term effects of a single dose of ivermectin on the human immune system.

BACKGROUND: Ivermectin is widely used in human and animal medicine to treat and prevent parasite nematode infections. It has been suggested that its mode of action requires the host immune system, as it is difficult to reproduce its clinical efficacy in vitro. We therefore studied the effects of a single dose of ivermectin (Stromectol®-0.15 mg/kg) on cytokine levels and immune cell gene expression in human volunteers. This dose reduces bloodstream microfilariae rapidly and for several months when given in mass drug administration programmes. METHODS: Healthy volunteers with no travel history to endemic regions were given 3-4 tablets, depending on their weight, of either ivermectin or a placebo. Blood samples were drawn immediately prior to administration, 4 h and 24 h afterwards, and complete blood counts performed. Serum levels of 41 cytokines and chemokines were measured using Luminex® and expression levels of 770 myeloid-cell-related genes determined using the NanoString nCounter®. Cytokine levels at 4 h and 24 h post-treatment were compared to the levels pre-treatment using simple t tests to determine if any individual results required further investigation, taking p = < 0.05 as the level of significance. NanoString data were analysed on the proprietary software, nSolver™. RESULTS: No significant differences were observed in complete blood counts or cytokine levels at either time point between people given ivermectin versus placebo. Only three genes showed a significant change in expression in peripheral blood mononuclear cells 4 h after ivermectin was given; there were no significant changes 24 h after drug administration or in polymorphonuclear cells at either time point. Leukocytes isolated from those participants given ivermectin showed no difference in their ability to kill Brugia malayi microfilariae in vitro. CONCLUSIONS: Overall, our data do not support a direct effect of ivermectin, when given at the dose used in current filarial elimination programmes, on the human immune system. Trial registration ClinicalTrials.gov NCT03459794 Registered 9th March 2018, Retrospectively registered https://clinicaltrials.gov/ct2/show/NCT03459794?term=NCT03459794&draw=2&rank=1 .

Management of Acute Lung Injury: Palmitoylethanolamide as a New Approach.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.

Alpha-defensins: risk factor for thrombosis in COVID-19 infection.

The inflammatory response to SARS/CoV-2 (COVID-19) infection may contribute to the risk of thromboembolic complications. α-Defensins, antimicrobial peptides released from activated neutrophils, are anti-fibrinolytic and prothrombotic in vitro and in mouse models. In this prospective study of 176 patients with COVID-19 infection, we found that plasma levels of α-defensins were elevated, tracked with disease progression/mortality or resolution and with plasma levels of interleukin-6 (IL-6) and D-dimers. Immunohistochemistry revealed intense deposition of α-defensins in lung vasculature and thrombi. IL-6 stimulated the release of α-defensins from neutrophils, thereby accelerating coagulation and inhibiting fibrinolysis in human blood, imitating the coagulation pattern in COVID-19 patients. The procoagulant effect of IL-6 was inhibited by colchicine, which blocks neutrophil degranulation. These studies describe a link between inflammation and the risk of thromboembolism, and they identify a potential new approach to mitigate this risk in patients with COVID-19 and potentially in other inflammatory prothrombotic conditions.

Flavonoids as inhibitors of human neutrophil elastase.

Elastase is a proteolytic enzyme belonging to the family of hydrolases produced by human neutrophils, monocytes, macrophages, and endothelial cells. Human neutrophil elastase is known to play multiple roles in the human body, but an increase in its activity may cause a variety of diseases. Elastase inhibitors may prevent the development of psoriasis, chronic kidney disease, respiratory disorders (including COVID-19), immune disorders, and even cancers. Among polyphenolic compounds, some flavonoids and their derivatives, which are mostly found in herbal plants, have been revealed to influence elastase release and its action on human cells. This review focuses on elastase inhibitors that have been discovered from natural sources and are biochemically characterised as flavonoids. The inhibitory activity on elastase is a characteristic of flavonoid aglycones and their glycoside and methylated, acetylated and hydroxylated derivatives. The presented analysis of structure-activity relationship (SAR) enables the determination of the chemical groups responsible for evoking an inhibitory effect on elastase. Further study especially of the in vivo efficacy and safety of the described natural compounds is of interest in order to gain better understanding of their health-promoting potential.

α1-Antitrypsin: Key Player or Bystander in Acute Respiratory Distress Syndrome?

Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar-capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.

Ivermectin reduces in vivo coronavirus infection in a mouse experimental model.

The objective of this study was to test the effectiveness of ivermectin for the treatment of mouse hepatitis virus (MHV), a type 2 family RNA coronavirus similar to SARS-CoV-2. Female BALB/cJ mice were infected with 6,000 PFU of MHV-A59 (group infected, n = 20) or infected and then immediately treated with a single dose of 500 µg/kg ivermectin (group infected + IVM, n = 20) or were not infected and treated with PBS (control group, n = 16). Five days after infection/treatment, the mice were euthanized and the tissues were sampled to assess their general health status and infection levels. Overall, the results demonstrated that viral infection induced typical MHV-caused disease, with the livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while mice treated with ivermectin showed a better health status with a lower viral load (23,192 AU; p < 0.05), with only a few having histopathological liver damage (p < 0.05). No significant differences were found between the group infected + IVM and control group mice (P = NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in the treated mice than in the infected animals. In conclusion, ivermectin diminished the MHV viral load and disease in the mice, being a useful model for further understanding this therapy against coronavirus diseases.

Neutrophils and Neutrophil Extracellular Traps Regulate Immune Responses in Health and Disease.

Neutrophils are first responders of antimicrobial host defense and sterile inflammation, and therefore, play important roles during health and disease [...].

Dipeptidyl peptidase 4 inhibitors: Applications in innate immunity?

Dipeptidyl peptidase (DPP)-4 inhibitors are a class of orally available, small molecule inhibitors that prolong the insulinotropic activity of the incretin hormone glucagon-like peptide-1 (GLP-1) and are highly effective for the treatment of Type-2 diabetes. DPP4 can also cleave several immunoregulatory peptides including chemokines. Emerging evidence continues to implicate DPP4 inhibitors as immunomodulators, with recent findings suggesting DPP4 inhibitors modify specific aspects of innate immunity. This review summarises recent insights into how DPP4 inhibitors could be implicated in endothelial, neutrophil and monocyte/macrophage mediated immunity. Additionally, this review highlights additional avenues of research with DPP4 inhibitors in the context of the COVID-19 pandemic.

Carboxypeptidase B blocks ex vivo activation of the anaphylatoxin-neutrophil extracellular trap axis in neutrophils from COVID-19 patients.

BACKGROUND: Thrombosis and coagulopathy are highly prevalent in critically ill patients with COVID-19 and increase the risk of death. Immunothrombosis has recently been demonstrated to contribute to the thrombotic events in COVID-19 patients with coagulopathy. As the primary components of immunothrombosis, neutrophil extracellular traps (NETs) could be induced by complement cascade components and other proinflammatory mediators. We aimed to explore the clinical roles of NETs and the regulation of complement on the NET formation in COVID-19. METHODS: We recruited 135 COVID-19 patients and measured plasma levels of C5, C3, cell-free DNA and myeloperoxidase (MPO)-DNA. Besides, the formation of NETs was detected by immunofluorescent staining and the cytotoxicity to vascular endothelial HUVEC cells was evaluated by CCK-8 assay. RESULTS: We found that the plasma levels of complements C3 and MPO-DNA were positively related to coagulation indicator fibrin(-ogen) degradation products (C3: r = 0.300, p = 0.005; MPO-DNA: r = 0.316, p = 0.002) in COVID-19 patients. Besides, C3 was positively related to direct bilirubin (r = 0.303, p = 0.004) and total bilirubin (r = 0.304, p = 0.005), MPO-DNA was positively related to lactate dehydrogenase (r = 0.306, p = 0.003) and creatine kinase (r = 0.308, p = 0.004). By using anti-C3a and anti-C5a antibodies, we revealed that the complement component anaphylatoxins in the plasma of COVID-19 patients strongly induced NET formation. The pathological effect of the anaphylatoxin-NET axis on the damage of vascular endothelial cells could be relieved by recombinant carboxypeptidase B (CPB), a stable homolog of enzyme CPB2 which can degrade anaphylatoxins to inactive products. CONCLUSIONS: Over-activation in anaphylatoxin-NET axis plays a pathological role in COVID-19. Early intervention in anaphylatoxins might help prevent thrombosis and disease progression in COVID-19 patients.

Probable positive effects of the photobiomodulation as an adjunctive treatment in COVID-19: A systematic review.

BACKGROUND: COVID-19, as a newly-emerged viral infection has now spread all over the world after originating in Wuhan, China. Pneumonia is the hallmark of the disease, with dyspnea in half of the patients and acute respiratory distress syndrome (ARDS) in up to one -third of the cases. Pulmonary edema, neutrophilic infiltration, and inflammatory cytokine release are the pathologic signs of this disease. The anti-inflammatory effect of the photobiomodulation (PBM) has been confirmed in many previous studies. Therefore, this review study was conducted to evaluate the direct effect of PBM on the acute lung inflammation or ARDS and also accelerating the regeneration of the damaged tissues. The indirect effects of PBM on modulation of the immune system, increasing the blood flow and oxygenation in other tissues were also considered. METHODOLOGY: The databases of PubMed, Cochrane library, and Google Scholar were searched to find the relevant studies. Keywords included the PBM and related terms, lung inflammation, and COVID-19 -related signs. Studies were categorized with respect to the target tissue, laser parameters, and their results. RESULTS: Seventeen related papers were included in this review. All of them were in animal models. They showed that the PBM could significantly decrease the pulmonary edema, neutrophil influx, and generation of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), intracellular adhesion molecule (ICAM), reactive oxygen species (ROS), isoform of nitric oxide synthase (iNOS), and macrophage inflammatory protein 2 (MIP-2)). CONCLUSION: Our findings revealed that the PBM could be helpful in reducing the lung inflammation and promoting the regeneration of the damaged tissue. PBM can increase the oxygenation indirectly in order to rehabilitate the affected organs. Thus, the infra-red lasers or light-emitting diodes (LEDs) are recommended in this regard.

Dapsone as treatment adjunct in ARDS.

Multiple pharmacological interventions tested over the last decades have failed to reduce ARDS mortality. This short note recounts past data indicating that (i) neutrophils home along an IL-8 gradient, (ii) in ARDS, massive neutrophil accumulation and degranulation in and along bronchoalveolar spaces contributes to damage and hypoxia, (iii) large increases in IL-8 are one of the chemotaxic signals drawing neutrophils to the ARDS lung, and (iv) old data from dermatology and glioblastoma research showed that the old drug against Hansen's disease, dapsone, inhibits neutrophils' chemotaxis to IL-8. Therefore dapsone might lower neutrophils' contributions to ARDS lung pathology. Dapsone can create methemoglobinemia that although rarely problematic it would be particularly undesirable in ARDS. The common antacid drug cimetidine lowers risk of dapsone related methemoglobinemia and should be given concomitantly.