A5040923815- Cystic Fibrosis Research Advances
- Neonatal Respiratory Health Research
- Ion Transport and Channel Regulation
- Tracheal and airway disorders
- Asthma and respiratory diseases
- Neuroscience of respiration and sleep
- Animal Nutrition and Physiology
- Physiological and biochemical adaptations
- Heavy Metal Exposure and Toxicity
- Ion channel regulation and function
- Inhalation and Respiratory Drug Delivery
- Trace Elements in Health
- Cardiovascular and exercise physiology
- Congenital Ear and Nasal Anomalies
- Respiratory viral infections research
- Adenosine and Purinergic Signaling
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Mercury impact and mitigation studies
- Pediatric health and respiratory diseases
- Respiratory Support and Mechanisms
- Connexins and lens biology
- Obstructive Sleep Apnea Research
- Ocular Surface and Contact Lens
- Biochemical Analysis and Sensing Techniques
- Advanced Chemical Sensor Technologies
Lung Institute
2016-2024
University of North Carolina at Chapel Hill
2013-2023
Indiana University School of Medicine
2004-2010
Pulmonary Associates
1985-2009
Ashok Leyland (India)
2009
Ashoka
2009
University Hospital of Lausanne
1997-1999
University of Lausanne
1999
North Carolina State University
1984-1992
Icahn School of Medicine at Mount Sinai
1984
Rationale: Identification of the specific cell types expressing CFTR (cystic fibrosis [CF] transmembrane conductance regulator) is required for precision medicine therapies CF. However, a full characterization expression in normal human airway epithelia missing. Objectives: To identify that contribute to and function within proximal–distal axis lung. Methods: Single-cell RNA (scRNA) sequencing (scRNA-seq) was performed on freshly isolated large small epithelial cells. scRNA situ...
Although loss of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl- channel function is common to all epithelia in (CF) patients, the severity disease varies different organs. We hypothesized that differences CF relate expression an "alternative" plasma membrane conductance. In mice [Cftr(-/-); homozygous for Ser-489 Xaa mutation], which do not express cAMP CFTR-mediated secretion, we surveyed organs exhibit a range Ca(2+)-mediated apical epithelial This alternative...
The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes an adenosine 3′,5′-monophosphate (cyclic AMP)—activated chloride channel. In (CF) patients, loss of CFTR function because a genetic mutation results in defective cyclic AMP—mediated secretion across epithelia. Because their potential role as animal model for CF, mice with targeted disruption the murine [CFTR(-/-)] were tested abnormalities epithelial transport. both freshly excised tissue from intestine and cultured...
Cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-dependent airway epithelial bicarbonate transport is hypothesized to participate in surface liquid pH regulation and contribute lung defense. We measured ionic composition apical (ASL) on polarized normal (NL) CF primary bronchial cell cultures under basal conditions, after cAMP stimulation, challenge with luminal acid loads. Under epithelia acidified ASL more rapidly than NL epithelia. Two regulatory paths that contributed were...
Genetic evidence supports a critical role for the epithelial sodium channel (ENaC) in both clearance of fetal lung liquid at birth and total body electrolyte homeostasis. Evidence from heterologous expression systems suggests that alphaENaC subunit is essential function, whereas residual function can be measured absence beta or gamma subunits. We generated mice without gammaENaC (gammaENaC -/-) to test this neonatal balance. Relative controls, (-/-) pups showed low urinary [K+] high [Na+]...
Two hypotheses have been proposed recently that offer different views on the role of airway surface liquid (ASL) in lung defense. The “compositional” hypothesis predicts ASL [NaCl] is kept low (<50 mM) by passive forces to permit antimicrobial factors act as a chemical “volume” volume (height) regulated isotonically active ion transport maintain efficient mechanical mucus clearance primary form To compare these hypotheses, we searched for roles for: (1) (surface tension, ciliary tip...
Nucleotides within the airway surface liquid (ASL) regulate epithelial ion transport rates by Ca(2+) -and protein kinase C-dependent mechanisms via activation of specific P2Y receptors. Extracellular adenine nucleotides also serve as precursors for adenosine, which promotes cyclic AMP-mediated cystic fibrosis transmembrane regulator chloride channel A(2b) adenosine A biological role extracellular ATP in ASL volume homeostasis has been suggested demonstration regulated release from epithelia....
We investigated the effect of homozygous genetic disruption murine cystic fibrosis transmembrane regulator (CFTR) gene on regulation rates Na+ absorption and Cl- secretion by nasal epithelia in (CF) mice. The basal vivo potential difference (PD; -28.8 +/- 1.8 mV, n = 10) amiloride-sensitive PD (delta 13.8 1.0 were raised CF mice compared with controls [-7.8 0.8 14 (basal); delta 4.5 0.7 (amiloride)], consistent transport. In vitro studies freshly excised confirmed that exhibited a greater...
MUC5AC, a major gel-forming mucin expressed in the lungs, is secreted at increased rates response to infectious agents, implying that mucins exert protective role against inhaled pathogens. However, epidemiological and pathological studies suggest excessive secretion causes airways obstruction inflammation. To determine whether MUC5AC alone produces airway and/or inflammation, we generated mouse model overexpressing Muc5ac mRNA ∼20-fold using rCCSP promoter. The cDNA was cloned from lungs...
Airways obstruction with thick, adherent mucus is a pathophysiologic and clinical feature of muco-obstructive respiratory diseases, including chronic obstructive pulmonary disease, asthma, cystic fibrosis (CF). Mucins, the dominant biopolymer in mucus, organize into complex polymeric networks via formation covalent disulfide bonds, which govern viscoelastic properties gel. For decades, inhaled N-acetylcysteine (NAC) has been used as mucolytic to reduce mucin bonds little, if any, therapeutic...
Unlike solid organs, human airway epithelia derive their oxygen from inspired air rather than the vasculature. Many pulmonary diseases are associated with intraluminal obstruction caused by aspirated foreign bodies, virus infection, tumors, or mucus plugs intrinsic to disease, including cystic fibrosis (CF). Consistent requirements for luminal O 2 , surrounding in chronic obstructive disease (COPD) lungs hypoxic. Despite these observations, effects of hypoxia (CH) on epithelial host defense...
Extracellular nucleotides are believed to be important regulators of ion transport in epithelial tissues as a result their ability activate cell surface receptors. Although numerous receptors that bind have been identified, the complexity this receptor family, combined with lack pharmacological agents specific for these receptors, has made assignment particular and ligands physiological responses difficult. Because ATP UTP appear equipotent equieffective regulating many epithelia, we tested...
Aldosterone-dependent epithelial sodium transport in the distal nephron is mediated by absorption of through highly selective, amiloride-sensitive channel (ENaC) made three homologous subunits (α, β, and γ). In human, autosomal recessive mutations α, or γENaC cause pseudohypoaldosteronism type 1 (PHA-1), a renal salt-wasting syndrome characterized severe hypovolemia, high plasma aldosterone, hyponatremia, life-threatening hyperkaliemia, metabolic acidosis. mouse, inactivation αENaC results...
Abstract Cystic fibrosis (CF) lung disease is characterized by persistent infection. Thickened (concentrated) mucus in the CF impairs airway clearance, which initiates bacterial However, airways have other mechanisms to prevent infection, including neutrophil-mediated killing. Therefore, we examined whether neutrophil motility and capture killing functions are impaired thickened mucus. Mucus of three concentrations, representative range normal (1.5 2.5% dry weight) CF-like (6.5%) mucus, was...
Extracellular nucleotides, signaling through P2 receptors, may act as local regulators of bone cell function. We investigated the effects nucleotide agonists [ATP, ADP, uridine triphosphate (UTP), and diphosphate] pyrophosphate (PPi, a key physiological inhibitor mineralization) on deposition mineralization collagenous matrix by primary osteoblasts derived from rat calvariae. Our results show that extracellular ATP, UTP, PPi strongly selectively blocked nodules; ADP diphosphate were without...