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In recent years, research has unveiled the significant role of hydrogen sulfide (H2S) in many physiological and pathological processes. The role of endogenous H2S, H2S donors, and inhibitors has been the subject of studies that have aimed to investigate this intriguing molecule. The mechanisms by which H2S contributes to different diseases, including inflammatory conditions, cardiovascular disease, viral infections, and neurological disorders, are complex. Despite noteworthy progress, several questions remain unanswered. H2S donors and inhibitors have shown significant therapeutic potential for various diseases. This review summarizes our current understanding of H2S-based therapeutics in inflammatory conditions, cardiovascular diseases, viral infections, and neurological disorders. [ABSTRACT FROM AUTHOR]

Substance P (SP), encoded by the Tac1 gene, has been shown to promote leukocyte infiltration and organ impairment in mice with sepsis. Neurokinin-1 receptor (NK1R) is the major receptor that mediates the detrimental impact of SP on sepsis. This investigation studied whether SP affects the expression of adhesion molecules, including intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1) on vascular endothelial cells in the liver and lungs, contributing to leukocyte infiltration in these tissues of mice with sepsis. Sepsis was induced by caecal ligation and puncture (CLP) surgery in mice. The actions of SP were inhibited by deleting the Tac1 gene, blocking NK1R, or combining these two methods. The activity of myeloperoxidase and the concentrations of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, were measured. The activity of myeloperoxidase and the concentration of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, increased in mice with CLP surgery-induced sepsis. Suppressing the biosynthesis of SP and its interactions with NK1R attenuated CLP surgery-induced alterations in the liver and lungs of mice. Our findings indicate that SP upregulates the expression of ICAM1 and VCAM1 on vascular endothelial cells in the liver and lungs, thereby increasing leukocyte infiltration in these tissues of mice with CLP surgery-induced sepsis by activating NK1R. [ABSTRACT FROM AUTHOR]

Animal production units produce and store many contaminants on-site, including organic dust (OD) and hydrogen sulfide (H2S). Workers in these settings report various respiratory disease symptoms. Both OD and H2S have shown to induce lung inflammation. However, impact of co-exposure to both H2S and OD has not been investigated. Therefore, we tested a hypothesis that pre-exposure to H2S modulates the innate inflammatory response of the lungs to organic dust. In a mouse model of H2S and organic dust extract (ODE) exposure, we assessed lung inflammation quantitatively. We exposed human airway epithelial and monocytic cells to medium or H2S alone or H2S followed by ODE and measured cell viability, oxidative stress, and other markers of inflammation. Exposure to 10 ppm H2S followed by ODE increased the lavage fluid leukocytes. However, exposure to 10 ppm H2S alone resulted in changes in tight junction proteins, an increase in mRNA levels of tlr2 and tlr4 as well as ncf1, ncf4, hif1α, and nrf2. H2S alone or H2S and ODE exposure decreased cell viability and increased reactive nitrogen species production. ODE exposure increased the transcripts of tlr2 and tlr4 in both in vitro and in vivo models, whereas increased nfkbp65 transcripts following exposure to ODE and H2S was seen only in in vitro model. H2S alone and H2S followed by ODE exposure increased the levels of IL-1β. We conclude that pre-exposure to H2S modulates lung innate inflammatory response to ODE.

This document is an editorial published in Frontiers in Immunology. It discusses the research topic of translational insights into mechanisms and therapy of organ dysfunction in sepsis and trauma. The authors highlight the importance of understanding the pathophysiology of trauma and critical illness and explore potential diagnostic markers and therapeutic interventions. The editorial covers three major fields of research: sepsis diagnosis and treatment, trauma, injury, and organ damage, and therapeutic interventions and drug repurposing. The authors conclude by expressing gratitude to the researchers, clinicians, and patients involved in this work and hope that the insights from these studies will contribute to improving care and outcomes for patients with critical illness. [Extracted from the article]

Neurokinin A (NKA) belongs to the tachykinin neuropeptide family. Its biological functions are primarily mediated by the neurokinin (NK)-2 receptor. NKA has been implicated in several inflammatory conditions. However, there are limited data about the mechanism of its pathogenetic action. Here, we investigated proinflammatory effects of NKA on peripheral immune cells using the mouse macrophage/ monocyte cell line RAW 264.7 and primary peritoneal macrophages. The signaling mechanistic pathways involved were also studied. In mouse macrophages with no detectable NK-2 receptors, NKA induces the upregulation of NK-1 but not NK-2 receptor expression. Furthermore, NKA engages this NK-1 receptor, resulting in inflammatory-like responses involving activation of the transcription factor nuclear factor (NF)-[kappa]B and induction of NF-[kappa]B-responsive proinflammatory chemokine expression. NKA activates NF-[kappa]B as evidenced by induced phosphorylation (leading to degradation) of its inhibitory protein I[kappa]B[alpha], increased cellular levels of the transactivation-active phospho([Ser.sup.276])-p65 and its nuclear translocation, as well as enhanced DNA-binding activity of NF-[kappa]B. These responses are specifically inhibited by selective NK-1 receptor antagonists but not NK-2 receptor antagonists, thereby excluding the role of NK-2 receptor. Further investigation on the upstream signaling mechanisms suggests that two NF-[kappa]B-activating pathways (extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase/protein kinase B) are activated by NKA. Specific inhibitors of the two pathways block NF-[kappa]B-dependent chemokine expression. The inhibitory effects are mediated through regulation of nuclear translocation, DNA-binding activity, and/or transactivation activity of NF-[kappa]B. Together, we provide novel evidence that NKA engages NK-1 receptors on mouse macrophages to elicit NF-[kappa]B-dependent cellular responses. The findings reveal cellular mechanisms that may underlie NKA-mediated inflammatory and immunological conditions. neuroimmunomodulation; tachykinins; leukocytes; chemokines; signaling transduction pathways

The neuropeptide substance P (SP), as a major mediator of neuroimmunomodulatory activity, modulates diverse functions of immune cells, including macrophages. In the current study, we focused on the yet uncertain role of SP in enhancing the inducible/inflammatory chemokine response of macrophages and the signaling mechanism involved. We studied the effect on the murine monocyte/macrophage cell line RAW 264.7 as well as isolated primary macrophages. Our data show that SP, at nanomolar concentrations, elicited selective chemokine production from murine macrophages. Among the chemokines examined, macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 are two major chemokines that were synthesized by macrophages in response to SP. Furthermore, SP treatment strongly induced the classic pathway of I[kappa]B-dependent NF-[kappa]B activation and enhanced DNA binding as well as transactivation activity of the transcription factor. SP-evoked transcriptional induction of chemokines was specific, since it was blocked by treatment with selective neurokinin-1 receptor antagonists. Moreover, SP stimulation of macrophages activated the ERK 1/2 and p38 MAPK but not JNKs. Blockade of these two MAPK pathways with specific inhibitors abolished SP-elicited nuclear translocation of phosphorylated NF-[kappa]B p65 and NF-[kappa]B-driven chemokine production, suggesting that the two MAPKs lie in the signaling pathways leading to the chemokine response. Collectively, our data demonstrate that SP enhances selective inflammatory chemokine production by murine macrophages via ERK/p38 MAPK-mediated NF-[kappa]B activation. neuropeptides; monocytes/macrophages; protein kinases; transcription factors; chemokines

Interaction of the neuropeptide substance P (SP) with its high-affinity neurokinin-1 receptor (NK1R) plays an important role in the pathophysiology of acute pancreatitis. SP is known to stimulate the production of chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1[alpha], and MIP-2 in pancreatic acinar cells via the activation of NF-[kappa]B. However, the signaling mechanisms by which the SP-NK1R interaction induces NF-[kappa]B activation and chemokine production remain unclear. To that end, in the present study, we investigated the participation of PKC in SP-induced chemokine production in pancreatic acinar cells. In this study, we showed that SP stimulated an early phosphorylation of PKC isoform PKC-[delta] followed by increased activation of MAPKKK MEKK1 and MAPK ERK and JNK as well as transcription factor NF-[kappa]B and activator protein-1 driven chemokine production. Depletion of PKC-[delta] with its inhibitor rottlerin or the specific PKC-[delta] translocation inhibitor peptide dose dependently decreased SP-induced PKC-[delta], MEKK1, ERK, JNK, NF-[kappa]B, and AP-1 activation. Moreover, rottlerin as well as PKC-[delta] translocation inhibitor inhibited SP-induced chemokine production in a concentration-dependent manner. We also demonstrated that PKC-[delta] activation was attenuated by CP96345, a selective NK1R antagonist, thus showing that PKC-[delta] activation was indeed mediated by SP in pancreatic acinar cells. These results show that PKC-[delta] is an important proinflammatory signal transducer for SP-NK1R-induced chemokine production in pancreatic acinar cells. protein kinse C-[delta]; mitogen-activated protein kinase kinase kinase-1; extracellular signal-regulated kinase; c-Jun N[H.sub.2]-terminal kinase; nuclear factor-[kappa]B; activator protein-1

Neuropeptides play an important role in the active communication between the nervous and immune systems. Substance P (SP) is a prominent neuropeptide involved in neurogenic inflammation and has been reported to exert various proinflammatory actions on inflammatory leukocytes including neutrophils. The present study further investigated the modulatory effect of SP (1 [micro]M) on chemokine production and chemokine receptor expression in primary mouse neutrophils. Our results showed that SP primed neutrophils for chemotactic responses not only to the CXC chemokine macrophage inflammatory protein (MIP)-2/CXCL2 but also to the CC chemokine MIP-I[alpha]CCL3. The activating effect of SP on neutrophils was further evidenced by upregulation of the CD11b integrin, the activation marker of neutrophils. SP induced both the mRNA and protein expression of the chemokines MIP-1[alpha]/CCL3 and MIP-2/CXCL2 in neutrophils and upregulated the chemokine receptors CC chemokine receptor (CCR)-1 and CXC chemokine receptor (CXCR)-2. This stimulatory effect on chemokine and chemokine receptor expression in neutrophils was further found to be neurokinin-1 receptor (NK-1R) specific. Pretreatment with selective NK-IR antagonists inhibited SP-triggered activation of neutrophils and chemokine and chemokine receptor upregulation. Moreover, SP-induced chemokine upregulation was NF-[kappa]B dependent. SP time dependently induced NF-[kappa]B p65 binding activity, I[kappa]Bp[alpaha] degradation, and NF-[kappa]B p65 nuclear translocation in neutrophils. Inhibition of NF-[kappa]B activation with its inhibitor Bay11-7082 (10 [micro]M) abolished SP-induced NF-[kappa]B binding activity and upregulation of MIP1[alpha]/CCL3 and MIP-2/CXCL2 in neutrophils. Together, these results suggest that SP exerts a direct stimulatory effect on the expression of chemokines and chemokine receptors in mouse neutrophils. The effect is NK-1R mediated, involving NF-[kappa]B activation. chemokines and receptors; neuro-immune interaction; neurokinin-1 receptor; primary leukocytes; NF-KB activation

We investigated the effect of a specific neurokinin-1 receptor (NK1R) antagonist, CP-96,345, on the regulation of the expression of adhesion molecules ICAM-1, VCAM-1, E-selectin, and P-selectin as well as leukocyte recruitment during acute pancreatitis (AP). AP was induced in male Balb/C mice by 10 consecutive hourly intraperitoneal injections of caerulein. In the treatment groups, CP-96,345 was administered at 2.5 mg/kg ip either 30 min before or 1 h after the first caerulein injection. Animals were killed, and the lungs and pancreas were isolated for RNA extraction and RT-PCR or for immunohistochemical staining. mRNA expression of the four adhesion molecules was upregulated in the pancreas during AP. Treatment with CP-96,345 effectively reduced the mRNA expression of P-selectin and E-selectin but not ICAM-1 and VCAM-1. In the lung, ICAM-1, E-selectin, and P-selectin mRNA expression increased during AP. Antagonist treatment suppressed this elevation. Similar expression patterns were seen in the immunohistochemical stainings. Intravital microscopy of the pancreatic microcirculation revealed the effect of CP-96,345 on leukocyte recruitment. The present study provides important information on the relationship between NK1R activation and the regulation of adhesion molecules. Also, this study points to the differential regulation of inflammation in the pancreas and lung with AP. tachykinins; pancreas; lung doi: 10.1152/ajpgi.00429.2006.

Recent studies have implied that hydrogen sulfide ([H.sub.2]S) plays a crucial role in several inflammatory conditions. However, so far little is known about the mechanism by which [H.sub.2]S provokes the inflammatory response in sepsis. Thus the aim of this study was to investigate if [H.sub.2]S regulates sepsis-associated systemic inflammation and production of proinflammatory mediators via the activation of NF-[kappa]B. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with DL-propargylglycine (PAG; 50 mg/kg ip), NaHS (10 mg/kg ip), or saline. PAG, an inhibitor of [H.sub.2]S formation, was administered either 1 h before or 1 h after CLP, whereas NaHS, an [H.sub.2]S donor, was given at the time of CLP. Some normal mice were given NaHS (10 mg/kg ip) to induce lung inflammation with or without pretreatment with the NF-[kappa]B inhibitor BAY 11-7082. Eight hours after CLP, both prophylactic and therapeutic administration of PAG significantly reduced the mRNA and protein levels of IL-1[beta], IL-6, TNF-[alpha], monocyte chemotactic protein-1, and macrophage inflammatory protein-2 in lung and liver coupled with decreased activation and translocation of NF-[kappa]B in lung and liver. Inhibition of [H.sub.2]S formation also significantly reduced lung permeability and plasma alanine aminotransferase activity. In contrast, injection of NaHS significantly aggravated sepsis-associated systemic inflammation and increased NF-[kappa]B activation. In addition, [H.sub.2]S-induced lung inflammation was blocked by BAY 11-7082. Therefore, [H.sub.2]S upregulates the production of proinflammatory mediators and exacerbates the systemic inflammation in sepsis through a mechanism involving NF-[kappa]B activation. DL-propargylglycine; nuclear factor-[kappa]B

Sepsis is a complex clinical syndrome resulting from a harmful host inflammatory response to infection. Chemokines and their receptors play a key role in the pathogenesis of sepsis. BX471 is a potent nonpeptide CC chemokine receptor-1 (CCR1) antagonist in both human and mouse. The aim of the present study was to evaluate the effect of prophylactic and therapeutic treatment with BX471 on cecal ligation and puncture-induced sepsis in the mouse and to investigate the underlying mechanisms. In sepsis induced by cecal ligation and puncture, treatment with BX471 significantly protected mice against lung and liver injury by attenuating MPO activity, an indicator of neutrophil recruitment in lungs and livers and attenuating lung and liver morphological changes in histological sections. Blocking CCR1 by BX471 also downregulated ICAM-1, P-selectin, and E-selectin expression at mRNA and protein levels in lungs and livers compared with placebo-treated groups. These findings suggest that blockage of CCR1 by specific antagonist may represent a promising strategy to prevent disease progression in sepsis. acute respiratory distress syndrome; multiple organ dysfunction syndrome; systemic inflammatory response syndrome