About

Russell Johns is a Professor in the Petroleum Engineering Department at Texas A&M University. He holds a Ph.D. and M.S. in Petroleum Engineering from Stanford University, obtained in 1992 and 1989 respectively, and a B.S. in Electrical Engineering from Northwestern University, earned in 1982. His research interests include enhanced oil recovery for conventional and unconventional reservoirs, miscible gas flooding, chemical flooding, low salinity water flooding, thermodynamics and phase behavior, well testing, and geothermal energy. He is a member of the National Academy of Engineering since 2025, an honorary member of the Society of Petroleum Engineers since 2025, and a distinguished member of the same society since 2009. Additionally, he served as the Editor in Chief for all Society of Petroleum Engineer Journals from 2018 to 2020 and has received numerous awards, including the Anthony F. Lucas Gold Medal in 2023 and the IOR Pioneer Award in 2022. His contributions to the field are recognized through his leadership roles, memberships, and awards within professional societies.

Research topics

• Immunology
• Medicine
• Internal medicine
• Biology
• Pathology
• Bioinformatics

Selected publications

• Disruption of Extracellular Signal-Regulated Kinase Partially Mediates Neonatal Isoflurane Anesthesia-Induced Changes in Dendritic Spines and Cognitive Function in Juvenile Mice

  International Journal of Molecular Sciences · 2025-01-24

  articleOpen accessSenior authorCorresponding

  There is a growing concern worldwide about the potential harmful effects of anesthesia on brain development, based on studies in both humans and animals. In infants, repeated anesthesia exposure is linked to learning disabilities and attention disorders. Similarly, laboratory studies in mice show that neonates exposed to general anesthesia experience long-term cognitive and behavioral impairments. Inhaled anesthetics affect the postsynaptic density (PSD)-95, discs large homolog, and zona occludens-1 (PDZ) domains. The disruption of the synaptic PSD95-PDZ2 domain-mediated protein interactions leads to a loss of spine plasticity and cognitive deficits in juvenile mice. The nitric oxide-mediated protein kinase-G signaling pathway enhances synaptic plasticity also by activating extracellular signal-regulated kinase, which subsequently phosphorylates cAMP-response element binding protein, a crucial transcription factor for memory formation. Exposure to isoflurane or postsynaptic density-95-PDZ2-wildtype peptides results in decreased levels of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated cAMP-response element binding protein (p-CREB), which are critical for synaptic plasticity and memory formation. Pizotifen treatment after isoflurane or postsynaptic density-95-PDZ2-wildtype peptide exposure in mice prevented decline in p-ERK levels, preserved learning and memory functions at 5 weeks of age, and maintained mushroom spine density at 7 weeks of age. Protein kinase-G activation by components of the nitric oxide signaling pathway leads to the stabilization of dendritic spines and synaptic connections. Concurrently, the ERK/CREB pathway, which is crucial for synaptic plasticity and memory consolidation, is supported and maintained by pizotifen, thereby preventing cognitive deficits caused in response to isoflurane or postsynaptic density-95-PDZ2-wildtype peptide exposure. Activation of ERK signaling cascade by pizotifen helps to prevent cognitive impairment and spine loss in response to postsynaptic density-95-PDZ2 domain disruption.

  PublisherOA PDFDOI

• Human resistin is critical to activation of the NLRP3 inflammasome in macrophages

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-14

  preprintOpen accessSenior authorCorresponding

  Elevated levels of human resistin (hResistin) have been associated with diverse inflammatory diseases, but the precise mechanisms through which hResistin's many inflammatory effects contribute to the progression of these diseases remain poorly understood. NLRP3 inflammasome activation is essential in many of these inflammatory conditions; however, there is an unmet explanation connecting hResistin with the NLRP3 inflammatory pathway. Here we describe a unique role of hResistin and its rodent homolog, resistin-like molecule alpha (RELMα) in priming and activating the NLRP3 inflammasome. Through qPCR and western blot analysis, we found that hResistin-dependent expression and secretion of high mobility group box 1 (HMGB1) in human macrophages primes the expression of NLRP3, pro-caspase-1, pro-interleukin(IL)-1β, and pro-IL-18. Co-immunoprecipitation showed that hResistin binds to Bruton's tyrosine kinase (BTK), which causes the kinase to autophosphorylate. Afterwards, BTK phosphorylates NLRP3, leading to its assembly and activation with subsequent cleavage of pro-caspase-1, pro-IL-1β, and pro-IL-18, causing initiation of the inflammasome cascade. The hResistin-dependent activation and secretion of IL-1β and IL-18 were critical to the proliferation of human pulmonary vascular smooth muscle cells. For confirmation in vivo, we studied rodent and human pulmonary hypertension (PH). Chronic hypoxia-induced PH in wild-type and RELMα KO mice showed RELMα-dependent upregulation of HMGB1, BTK, and NLRP3 in mouse lung and RELMα was linked to vascular remodeling pathways. Immunohistochemistry revealed that the majority of NLRP3-expressing cells were macrophages and the colocalization of hResistin, BTK, and NLRP3 in macrophages was increased in PH patients' lungs. Our work reveals a novel immune mechanism demonstrating hResistin is essential to the priming and activation of NLRP3. Inhibiting NLRP3 activation by blocking hResistin with a human monoclonal antibody suggests a likely therapeutic pathway for NLRP3-driven inflammatory diseases.

  PublisherDOI

• The Potential Role of Interactions Between Endothelium and Smooth Muscle in Pulmonary Vascular Physiology and Pathophysiology

  2024-10-23

  book-chapter

  The endothelium creates a nonthrombogenic, semipermeable barrier between the bloodstream and all extravascular tissues and fluid compartments in the body. The surface of the endothelial cell is composed of a vast array of enzymes, transport proteins, and receptors that are in direct contact with the bloodstream. During the last decade studies of the endothelium have played a vital role in expanding our knowledge of vascular regulation. Major areas of interest have been permeability characteristics: transport of both small and large molecules, inactivation of vasoactive compounds, production of vasoactive substances, and metabolism of arachidonic acid (Bassingthwaighte et al., 1985; Gillis and Pitt, 1982; Furchgott, 1984; Moneada et al., 1977; Pearson et al., 1978; Weksler et al., 1977; Grega et al., 1986; Ryan, 1986; Shepro, 1986). The endothelium exerts an influence on blood pressure, hemostasis, growth and cytodifferentiation, the vascular response to injury, chemotaxis, and blood pH among others.

  PublisherDOI

• Resistin predicts disease severity and survival in patients with pulmonary arterial hypertension

  Respiratory Research · 2024-06-06 · 3 citations

  articleOpen accessSenior author

  BACKGROUND: Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance, followed by right ventricular hypertrophy and failure. Despite considerable advancements in PAH treatment prognosis remains poor. We aim to evaluate the potential for using the cytokine resistin as a genetic and biological marker for disease severity and survival in a large cohort of patients with PAH. METHODS: Biospecimens, clinical, and genetic data for 1121 adults with PAH, including 808 with idiopathic PAH (IPAH) and 313 with scleroderma-associated PAH (SSc-PAH), were obtained from a national repository. Serum resistin levels were measured by ELISA, and associations between resistin levels, clinical variables, and single nucleotide polymorphism genotypes were examined with multivariable regression models. Machine-learning (ML) algorithms were applied to develop and compare risk models for mortality prediction. RESULTS: Resistin levels were significantly higher in all PAH samples and PAH subtype (IPAH and SSc-PAH) samples than in controls (P < .0001) and had significant discriminative abilities (AUCs of 0.84, 0.82, and 0.91, respectively; P < .001). High resistin levels (above 4.54 ng/mL) in PAH patients were associated with older age (P = .001), shorter 6-min walk distance (P = .001), and reduced cardiac performance (cardiac index, P = .016). Interestingly, mutant carriers of either rs3219175 or rs3745367 had higher resistin levels (adjusted P = .0001). High resistin levels in PAH patients were also associated with increased risk of death (hazard ratio: 2.6; 95% CI: 1.27-5.33; P < .0087). Comparisons of ML-derived survival models confirmed satisfactory prognostic value of the random forest model (AUC = 0.70, 95% CI: 0.62-0.79) for PAH. CONCLUSIONS: This work establishes the importance of resistin in the pathobiology of human PAH. In line with its function in rodent models, serum resistin represents a novel biomarker for PAH prognostication and may indicate a new therapeutic avenue. ML-derived survival models highlighted the importance of including resistin levels to improve performance. Future studies are needed to develop multi-marker assays that improve noninvasive risk stratification.

  PublisherOA PDFDOI

• G‐protein‐coupled receptor 41 in cardiomyocytes: Effect of butyrate on intracellular Ca ²⁺ and sarcomere shortening

  The FASEB Journal · 2024-12-09 · 1 citations

  article

  Abstract G‐protein‐coupled receptor 41 (GPR41) is a Gα i ‐coupled receptor activated by short‐chain fatty acids (SCFAs). Here, we tested that GPR41 is also expressed in cardiomyocytes and exerts a direct negative inotropic effect when activated by SCFA butyrate. Primary cardiomyocytes were isolated from wild‐type (WT) and GPR41 knockout (GPR41 −/− ) adult mice and intracellular Ca 2+ concentration and cell shortening were measured using the IonOptix system. RNA localization (RNAScope), quantitative real‐time polymerase chain reaction (qRT‐PCR), immunofluorescence staining, and western blot were used to examine the expression of GPR41 in adult primary cardiomyocytes of WT and GPR41 −/− mice. The effect of butyrate on shortening and intracellular Ca 2+ transient via GPR41 was also tested in cardiomyocytes. We demonstrated for the first time the presence of GPR41s on cardiomyocytes. Butyrate dose‐dependently decreased cell shortening and the amplitude of intracellular Ca 2+ transients in cardiomyocytes from WT but not GPR41 −/− mice. In WT cardiomyocytes, butyrate decreased caffeine‐mediated amplitudes of intracellular Ca 2+ transients from the sarcoplasmic reticulum (SR). Moreover, the inhibitory effects of butyrate on cell shortening and intracellular Ca 2+ were pertussis toxin (PTX)‐sensitive. Finally, butyrate decreased the activity of sarcoendoplasmic reticulum Ca 2+ ‐ATPase (SERCA) and cellular 3′‐5′‐cyclic adenosine monophosphate (cAMP) content. In conclusion, GPR41 is expressed on cardiomyocytes. Butyrate, a known GPR41 agonist, reduces cardiomyocyte shortening and intracellular Ca 2+ transient via decreasing Ca 2+ content in the SR by inhibiting SERCA activity in a PTX‐dependent manner. These findings establish that GPR41 is directly activated by SCFAs to decrease contraction and intracellular Ca 2+ transient, highlighting the potential inhibitory role of GPR41 in cardiomyocytes.

  PublisherDOI

• Resistin Pathway as Novel Mechanism of Post-lung Transplantation Bronchial Stenosis

  Journal of Bronchology & Interventional Pulmonology · 2023-05-19 · 1 citations

  articleSenior author

  BACKGROUND: Bronchial stenosis remains a significant source of morbidity among lung transplant recipients. Though infection and anastomotic ischemia have been proposed etiologies of the development of bronchial stenosis, the pathophysiologic mechanism has not been well elucidated. METHODS: In this single-centered prospective study, from January 2013 through September 2015, we prospectively collected bronchoalveolar lavage (BAL) and endobronchial epithelial brushings from the direct anastomotic site of bronchial stenosis of bilateral lung transplant recipients who developed unilateral post-transplant bronchial stenosis. Endobronchial epithelial brushings from the contralateral anastomotic site without bronchial stenosis and BAL from bilateral lung transplant recipients who did not develop post-transplant bronchial stenosis were used as controls. Total RNA was isolated from the endobronchial brushings and real-time polymerase chain reaction reactions were performed. Electrochemiluminescence biomarker assay was used to measure 10 cytokines from the BAL. RESULTS: Out of 60 bilateral lung transplant recipients, 9 were found to have developed bronchial stenosis with 17 samples adequate for analysis. We observed a 1.56 to 70.8 mean-fold increase in human resistin gene expression in the anastomotic bronchial stenosis epithelial cells compared with nonstenotic airways. Furthermore, IL-1β (21.76±10.96 pg/mL; control 0.86±0.44 pg/mL; P <0.01) and IL-8 levels (990.56±326.60 pg/mL; control 20.33±1.17 pg/mL; P <0.01) were significantly elevated in the BAL of the lung transplant patients who developed anastomotic bronchial stenosis. CONCLUSION: Our data suggest that the development of postlung transplantation bronchial stenosis may be in part mediated through the human resistin pathway by IL-1β induced transcription factor nuclear factor-κβ activation and downstream upregulation of IL-8 in alveolar macrophages. Further study is needed in the larger patient cohorts and to determine its potential therapeutic role in the management of post-transplant bronchial stenosis.

  PublisherDOI

• Human Resistin Induces Cardiac Dysfunction in Pulmonary Hypertension

  Journal of the American Heart Association · 2023-03-17 · 29 citations

  articleOpen accessSenior author

  Background Cardiac failure is the primary cause of death in most patients with pulmonary arterial hypertension (PH). As pleiotropic cytokines, human resistin (Hresistin) and its rodent homolog, resistin‐like molecule α, are mechanistically critical to pulmonary vascular remodeling in PH. However, it is still unclear whether activation of these resistin‐like molecules can directly cause PH‐associated cardiac dysfunction and remodeling. Methods and Results In this study, we detected Hresistin protein in right ventricular (RV) tissue of patients with PH and elevated resistin‐like molecule expression in RV tissues of rodents with RV hypertrophy and failure. In a humanized mouse model, cardiac‐specific Hresistin overexpression was sufficient to cause cardiac dysfunction and remodeling. Dilated hearts exhibited reduced force development and decreased intracellular Ca 2+ transients. In the RV tissues overexpressing Hresistin, the impaired contractility was associated with the suppression of protein kinase A and AMP‐activated protein kinase. Mechanistically, Hresistin activation triggered the inflammation mediated by signaling of the key damage‐associated molecular pattern molecule high‐mobility group box 1, and subsequently induced pro‐proliferative Ki67 in RV tissues of the transgenic mice. Intriguingly, an anti‐Hresistin human antibody that we generated protected the myocardium from hypertrophy and failure in the rodent PH models. Conclusions Our data indicate that Hresistin is expressed in heart tissues and plays a role in the development of RV dysfunction and maladaptive remodeling through its immunoregulatory activities. Targeting this signaling to modulate cardiac inflammation may offer a promising strategy to treat PH‐associated RV hypertrophy and failure in humans.

  PublisherOA PDFDOI

• Isoflurane Disrupts Postsynaptic Density-95 Protein Interactions Causing Neuronal Synapse Loss and Cognitive Impairment in Juvenile Mice via Canonical NO-mediated Protein Kinase-G Signaling

  Anesthesiology · 2022-05-03 · 10 citations

  articleOpen accessSenior author

  BACKGROUND: Inhalational anesthetics are known to disrupt PDZ2 domain-mediated protein-protein interactions of the postsynaptic density (PSD)-95 protein. The aim of this study is to investigate the underlying mechanisms in response to early isoflurane exposure on synaptic PSD-95 PDZ2 domain disruption that altered spine densities and cognitive function. The authors hypothesized that activation of protein kinase-G by the components of nitric oxide (NO) signaling pathway constitutes a mechanism that prevents loss of early dendritic spines and synapse in neurons and cognitive impairment in mice in response to disruption of PDZ2 domain of the PSD-95 protein. METHODS: Postnatal day 7 mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active PSD-95 wild-type PDZ2 peptide or soluble guanylyl cyclase activator YC-1 along with their respective controls. Primary neurons at 7 days in vitro were exposed to isoflurane or PSD-95 wild-type PDZ2 peptide for 4 h. Coimmunoprecipitation, spine density, synapses, cyclic guanosine monophosphate-dependent protein kinase activity, and novel object recognition memory were assessed. RESULTS: Exposure of isoflurane or PSD-95 wild-type PDZ2 peptide relative to controls causes the following. First, there is a decrease in PSD-95 coimmunoprecipitate relative to N-methyl-d-aspartate receptor subunits NR2A and NR2B precipitate (mean ± SD [in percentage of control]: isoflurane, 54.73 ± 16.52, P = 0.001; and PSD-95 wild-type PDZ2 peptide, 51.32 ± 12.93, P = 0.001). Second, there is a loss in spine density (mean ± SD [spine density per 10 µm]: control, 5.28 ± 0.56 vs. isoflurane, 2.23 ± 0.67, P < 0.0001; and PSD-95 mutant PDZ2 peptide, 4.74 ± 0.94 vs. PSD-95 wild-type PDZ2 peptide, 1.47 ± 0.87, P < 0.001) and a decrease in synaptic puncta (mean ± SD [in percentage of control]: isoflurane, 41.1 ± 14.38, P = 0.001; and PSD-95 wild-type PDZ2 peptide, 50.49 ± 14.31, P < 0.001). NO donor or cyclic guanosine monophosphate analog prevents the spines and synapse loss and decline in the cyclic guanosine monophosphate-dependent protein kinase activity, but this prevention was blocked by soluble guanylyl cyclase or protein kinase-G inhibitors in primary neurons. Third, there were deficits in object recognition at 5 weeks (mean ± SD [recognition index]: male, control, 64.08 ± 10.57 vs. isoflurane, 48.49 ± 13.41, P = 0.001, n = 60; and female, control, 67.13 ± 11.17 vs. isoflurane, 53.76 ± 6.64, P = 0.003, n = 58). Isoflurane-induced impairment in recognition memory was preventable by the introduction of YC-1. CONCLUSIONS: Activation of soluble guanylyl cyclase or protein kinase-G prevents isoflurane or PSD-95 wild-type PDZ2 peptide-induced loss of dendritic spines and synapse. Prevention of recognition memory with YC-1, a NO-independent activator of guanylyl cyclase, supports a role for the soluble guanylyl cyclase mediated protein kinase-G signaling in countering the effects of isoflurane-induced cognitive impairment.

  PublisherOA PDFDOI

• Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs

  EBioMedicine · 2022 · 83 citations

  • Pathology
  • Medicine
  • Immunology

  BACKGROUND: Thromboembolism is a life-threatening manifestation of coronavirus disease 2019 (COVID-19). We investigated a dysfunctional phenotype of vascular endothelial cells in the lungs during COVID-19. METHODS: We obtained the lung specimens from the patients who died of COVID-19. The phenotype of endothelial cells and immune cells was examined by flow cytometry and immunohistochemistry (IHC) analysis. We tested the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the endothelium using IHC and electron microscopy. FINDINGS: The autopsy lungs of COVID-19 patients exhibited severe coagulation abnormalities, immune cell infiltration, and platelet activation. Pulmonary endothelial cells of COVID-19 patients showed increased expression of procoagulant von Willebrand factor (VWF) and decreased expression of anticoagulants thrombomodulin and endothelial protein C receptor (EPCR). In the autopsy lungs of COVID-19 patients, the number of macrophages, monocytes, and T cells was increased, showing an activated phenotype. Despite increased immune cells, adhesion molecules such as ICAM-1, VCAM-1, E-selectin, and P-selectin were downregulated in pulmonary endothelial cells of COVID-19 patients. Notably, decreased thrombomodulin expression in endothelial cells was associated with increased immune cell infiltration in the COVID-19 patient lungs. There were no SARS-CoV-2 particles detected in the lung endothelium of COVID-19 patients despite their dysfunctional phenotype. Meanwhile, the autopsy lungs of COVID-19 patients showed SARS-CoV-2 virions in damaged alveolar epithelium and evidence of hypoxic injury. INTERPRETATION: Pulmonary endothelial cells become dysfunctional during COVID-19, showing a loss of thrombomodulin expression related to severe thrombosis and infiltration, and endothelial cell dysfunction might be caused by a pathologic condition in COVID-19 patient lungs rather than a direct infection with SARS-CoV-2. FUNDING: This work was supported by the Johns Hopkins University, the American Heart Association, and the National Institutes of Health.

  PublisherDOI

• The inflammatory role of dysregulated IRS2 in pulmonary vascular remodeling under hypoxic conditions

  American Journal of Physiology-Lung Cellular and Molecular Physiology · 2021-06-30 · 16 citations

  articleOpen access

  Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown previously that insulin receptor substrate 2 (IRS2), a molecule highly critical to insulin resistance and metabolism, has an anti-inflammatory role in Th2-skewed lung inflammation and pulmonary vascular remodeling. Here, we investigated the hypothesis that IRS2 has an immunomodulatory role in human and experimental PH. Expression analysis showed that IRS2 was significantly decreased in the pulmonary vasculature of patients with pulmonary arterial hypertension and in rat models of PH. In mice, genetic ablation of IRS2 enhanced the hypoxia-induced signaling pathway of Akt and Forkhead box O1 (FOXO1) in the lung tissue and increased pulmonary vascular muscularization, proliferation, and perivascular macrophage recruitment. Furthermore, mice with homozygous IRS2 gene deletion showed a significant gene dosage-dependent increase in pulmonary vascular remodeling and right ventricular hypertrophy in response to hypoxia. Functional studies with bone marrow-derived macrophages isolated from homozygous IRS2 gene-deleted mice showed that hypoxia exposure led to enhancement of the Akt and ERK signaling pathway followed by increases in the pro-PH macrophage activation markers, vascular endothelial growth factor-A and arginase 1. Our data suggest that IRS2 contributes to anti-inflammatory effects by regulating macrophage activation and recruitment, which may limit the vascular inflammation, remodeling, and right ventricular hypertrophy that are seen in PH pathology. Restoring the IRS2 pathway may be an effective therapeutic approach for the treatment of PH and right heart failure.

  PublisherOA PDFDOI

Recent grants

• Targeting resitin and RELM-beta to treat pulmonary hypertension

  NIH · $4.9M · 2014–2020

• DAMP Signaling Mediates HIMF-induced Pulmonary Hypertension

  NIH · $1.8M · 2018–2023

• NIH Grant R01GM049111

  NIH · $5.0M · 2011

• NIH Grant P50HL084946

  NIH · $41.5M · 2014

• NIH Grant R29HL039706

  NIH · $498k · 1993

Frequent coauthors

• John Skinner

  Johns Hopkins University

  122 shared

• Feng Tao

  116 shared

• Yuan‐Xiang Tao

  Rutgers, The State University of New Jersey

  114 shared

• Andrew D. Shore

  Royal Society of Chemistry

  54 shared

• Dechun Li

  Xuzhou Central Hospital

  52 shared

• Martin A. Makary

  Johns Hopkins Medicine

  52 shared

• Chunling Fan

  Heilongjiang Bayi Agricultural University

  48 shared

• Kazuyo Yamaji-Kegan

  University of Maryland, Baltimore

  47 shared

Labs

• Petroleum Engineering, Texas A&M UniversityPI

Awards & honors

• Anthony F. Lucas Gold Medal, AIME (2023)
• IOR Pioneer Award, Society of Petroleum Engineers (2022)
• Editor in Chief for all Society of Petroleum Engineer Journa…
• International Award in Reservoir Description and Dynamics, S…
• Faculty Pipeline Award, Society of Petroleum Engineers (2013…