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author:("Ahmad, afab")
1.  Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation 
Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence.
Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, were instilled into the trachea. Arterial O2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma analyzed for prothrombin, thrombin-antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin.
Airway obstruction in the form of fibrin-containing casts were evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid.
Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury.
PMCID: PMC3775856  PMID: 23727623
Sulfur mustard; inhalation; lung injury; TFPI; airway; coagulation
2.  Menacanthus palmai, a new species of chewing louse (Menoponidae: Amblycera: Phthiraptera) from the Coturnix coromandelica 
The new species Menacanthus palmai collected from Coturnix coromandelica (Gmelin), in Rampur district (UP), India, is described and illustrated. Morphologically the new species is close to M. abdominalis from Coturnix coturnix but differs in having long pointed ventral processes on the postero-medial angles of the second to fifth pleurites. Furthermore, these two species also differ in the number of tergal and sternal abdominal setae, and the morphology of the male genitalia. Another species, Menacanthus pallipes from C. chinensis, does not have ventral processes on the postero-medial angles of pleurites.
PMCID: PMC3793084  PMID: 24431583
Chewing lice; Biting lice; New louse; Louse taxonomy; Menacanthus
3.  In vitro Cell Culture Model for Toxic Inhaled Chemical Testing 
Cell cultures are indispensable to develop and study efficacy of therapeutic agents, prior to their use in animal models. We have the unique ability to model well differentiated human airway epithelium and heart muscle cells. This could be an invaluable tool to study the deleterious effects of toxic inhaled chemicals, such as chlorine, that can normally interact with the cell surfaces, and form various byproducts upon reacting with water, and limiting their effects in submerged cultures. Our model using well differentiated human airway epithelial cell cultures at air-liqiuid interface circumvents this limitation as well as provides an opportunity to evaluate critical mechanisms of toxicity of potential poisonous inhaled chemicals. We describe enhanced loss of membrane integrity, caspase release and death upon toxic inhaled chemical such as chlorine exposure. In this article, we propose methods to model chlorine exposure in mammalian heart and airway epithelial cells in culture and simple tests to evaluate its effect on these cell types.
PMCID: PMC4047665  PMID: 24837339
Bioengineering; Issue 87; air-liquid interface; chlorine exposure; toxic inhaled chemicals; Transepithelial Electrical Resistance; Immunocytochemistry
4.  Differential Regulation of Pulmonary Vascular Cell Growth by Hypoxia-Inducible Transcription Factor–1α and Hypoxia-Inducible Transcription Factor–2α 
Hypoxia-inducible transcription factors HIF-1α and HIF-2α can contribute to pulmonary hypertension and vascular remodeling, but their mechanisms remain unknown. This study investigated the role of HIF-1α and HIF-2α in pulmonary artery endothelial and smooth muscle cells. The exposure of human pulmonary artery endothelial cells (HPAECs) to hypoxia (10% O2 or 5% O2) increased proliferation over 48 hours, compared with cells during normoxia (21% O2). The adenovirus-mediated overexpression of HIF-2α that is transcriptionally active during normoxia (mutHIF-2α) increased HPAEC proliferation, whereas the overexpression of HIF-1α, which is transcriptionally active during normoxia (mutHIF-1α), exerted no effect. The knockdown of HIF-2α decreased proliferation during both hypoxia and normoxia. Both HIFs increased migration toward fibrinogen, used as a chemoattractant. In an angiogenesis tube formation assay, mutHIF-2α–transduced cells demonstrated increased tube formation, compared with the mutHIF-1α–transduced cells. In addition, the tubes formed in HIF-2α–transduced cells were more enduring than those in the other groups. In human pulmonary artery smooth muscle cells (HPASMCs), chronic exposure to hypoxia increased proliferation, compared with cells during normoxia. For HPASMCs transduced with adenoviral HIFs, HIF-1α increased proliferation, whereas HIF-2α exerted no such effect. Thus, HIF-1α and HIF-2α exert differential effects in isolated cells of the human pulmonary vasculature. This study demonstrates that HIF-2α plays a predominant role in the endothelial growth pertinent to the remodeling process. In contrast, HIF-1α appears to play a major role in pulmonary smooth muscle growth. The selective targeting of each HIF in specific target cells may more effectively counteract hypoxic pulmonary hypertension and vascular remodeling.
PMCID: PMC3727885  PMID: 23492195
HIF-2α; hypoxia; proliferation; endothelial; pulmonary
5.  Adenosine A2A receptor-dependent proliferation of pulmonary endothelial cells is mediated through calcium mobilization, PI3-kinase and ERK1/2 pathways 
Hypoxia and HIF-2α-dependent A2A receptor expression and activation increase proliferation of human lung microvascular endothelial cells (HLMVECs). This study was undertaken to investigate the signaling mechanisms that mediate the proliferative effects of A2A receptor. A2A receptor-mediated proliferation of HLMVECs was inhibited by intracellular calcium chelation, and by specific inhibitors of ERK1/2 and PI3-kinase (PI3K). The adenosine A2A receptor agonist CGS21680 caused intracellular calcium mobilization in controls and, to a greater extent, in A2A receptor-overexpressing HLMVECs. Adenoviral-mediated A2A receptor overexpression as well as receptor activation by CGS21680 caused increased PI3K activity and Akt phosphorylation. Cells overexpressing A2A receptor also manifested enhanced ERK1/2 phosphorylation upon CGS21680 treatment. A2A receptor activation also caused enhanced cAMP production. Likewise, treatment with 8Br-cAMP increased PI3K activity. Hence A2A receptor-mediated cAMP production and PI3K and Akt phosphorylation are potential mediators of the A2A-mediated proliferative response of HLMVECs. Cytosolic calcium mobilization and ERK1/2 phosphorylation are other critical effectors of HLMVEC proliferation and growth. These studies underscore the importance of adenosine A2A receptor in activation of survival and proliferative pathways in pulmonary endothelial cells that are mediated through PI3K/Akt and ERK1/2 pathways.
PMCID: PMC4046330  PMID: 23583199
adenosine; A2A receptor; microvascular endothelial cells; pulmonary; intracellular calcium; PI3K; ERK1/2
6.  Tissue Factor Signals Airway Epithelial Basal Cell Survival via Coagulation and Protease-Activated Receptor Isoforms 1 and 2 
Tissue factor (TF) initiates the extrinsic coagulation cascade and is a high-affinity receptor for coagulation factor VII. TF also participates in protease-activated receptor (PAR)1 and PAR2 activation. Human epithelial basal cells were previously purified on the basis of TF expression. The purpose of this study was to determine if tracheobronchial epithelial basal cell–associated TF drives coagulation and/or activates PARs to promote basal cell functions. We used human tracheobronchial tissues to isolate human airway epithelial cells using specific cell surface markers by flow cytometry and studied TF expression by immunostaining. TF-dependent fibrin network formation was observed by confocal and scanning electron microscopy. TF knockdown was done using short hairpin RNA, and TF mRNA was measured using quantitative RT-PCR. We found that 97 ± 5% of first-passage human tracheobronchial epithelial cells were basal cells, and 100% of these basal cells expressed TF. Basal cell–associated TF was active, but TF activity was dependent on added extrinsic coagulation cascade factors. TF inhibition caused basal cell apoptosis and necrosis. This was due to two parallel but interdependent TF-regulated processes: failure to generate a basal cell–associated fibrin network and suboptimal PAR1 and PAR2 activity. The data indicate that membrane surface TF mediates airway epithelial basal cell attachment, which maintains cell survival and mitotic potential. The implications of these findings are discussed in the context of basal cell–associated TF activity in normal and injured tissues and of the potential for repair of airway epithelium in lung disease.
PMCID: PMC3547080  PMID: 23065128
tissue factor; epithelium; clotting; fibrin; tracheobronchial
7.  Interaction and Localization of Synthetic Nanoparticles in Healthy and Cystic Fibrosis Airway Epithelial Cells: Effect of Ozone Exposure 
Nanoparticles (NPs) produced by nanotechnology processes have taken the field of medicine by storm. Concerns about safety of these NPs in humans, however, have recently been raised. Although studies of NP toxicity have focused on lung disease the mechanistic link between NP exposure and lung injury remained unclear. This is primarily due to a lack of availability of appropriate airway disease models and sophisticated microscopic techniques to study nano-sized particulate delivery and resulting responses.
Air–liquid interface (ALI) cultures of non-cystic fibrosis (CF) and CF airway epithelial cells were exposed to the FITC-labeled NPs using a PennCentury microsprayer™. Uptake of NPs was assessed by FACS. Laser scanning microscopy (LSM) was performed and the images were analyzed by an advanced imaging software to study particle deposition and uptake.
Flow cytometry data revealed that CF cells accumulated increased amounts of NPs. The increased NP uptake could be attributed to the reduced CF transmembrane conductance regulator (CFTR) function as a similar increased retention/uptake was observed in cells whose CFTR expression was downregulated by antisense oligonucleotide. NPs alone did not induce pro-inflammatory cytokine release or cell death. The cell culture system was sensitive to ozone but exposure to the uncoated synthetic NPs used in this study, did not cause any synergistic or suppressive effects. LSM imaging and subsequent image restoration further indicated particle uptake and intracellular localization. Exposure to ozone increased nuclear uptake in both non-CF and CF cells.
Our findings demonstrate the uptake of NPs using ALI cultures of non-CF and CF airway epithelial cells. The NPs used here were useful in demonstrating uptake by airway epithelial cells without causing adverse effects in presence or absence of ozone. However, to totally exclude toxic effects, chronic studies under in vivo conditions using coated particulates are required.
PMCID: PMC3311910  PMID: 22007674
aerosol distribution; modeling; toxicology
8.  Hypoxia-Inducible Factor Regulates Expression of Surfactant Protein in Alveolar Type II Cells In Vitro 
Alveolar type II (ATII) cells cultured at an air–liquid (A/L) interface maintain differentiation, but they lose these properties when they are submerged. Others showed that an oxygen tension gradient develops in the culture medium as ATII cells consume oxygen. Therefore, we wondered whether hypoxia inducible factor (HIF) signaling could explain differences in the phenotypes of ATII cells cultured under A/L interface or submerged conditions. ATII cells were isolated from male Sprague-Dawley rats and cultured on inserts coated with a mixture of rat-tail collagen and Matrigel, in medium including 5% rat serum and 10 ng/ml keratinocyte growth factor, with their apical surfaces either exposed to air or submerged. The A/L interface condition maintained the expression of surfactant proteins, whereas that expression was down-regulated under the submerged condition, and the effect was rapid and reversible. Under submerged conditions, there was an increase in HIF1α and HIF2α in nuclear extracts, mRNA levels of HIF inducible genes, vascular endothelial growth factor, glucose transporter–1 (GLUT1), and the protein level of pyruvate dehydrogenase kinase isozyme–1. The expression of surfactant proteins was suppressed and GLUT1 mRNA levels were induced when cells were cultured with 1 mM dimethyloxalyl glycine. The expression of surfactant proteins was restored under submerged conditions with supplemented 60% oxygen. HIF signaling and oxygen tension at the surface of cells appears to be important in regulating the phenotype of rat ATII cells.
PMCID: PMC3262688  PMID: 21454802
HIF; ATII cells; surfactant proteins; VEGF; GLUT1
9.  Prevalence of Myrsidea salimalii (Amblycera: Phthiraptera) on striated babblers (Turdoides earlei) (Timaliidae: Passeriformes: Aves) 
Survey of literature showed that the population characteristics of the phthirapterans parasitizing striated babblers deserved investigation. Hence, 30 birds were examined during 2007–2009 in district Rampur U.P. The prevalence of an amblyceran louse, Myrsidea salimalii on striated babblers was 40%. The mean intensity of infestation and the sample mean abundance were 33.5 and 13.4, respectively. The variance to mean ratio of the population exceeded unity (36.24). The frequency distribution pattern of the louse was aggregated but did not conform to the negative binomial model. Females outnumbered the males in natural condition (M:F—1:1.4) while the nymphal population had an edge over adult population (A:N—1:1.3).
PMCID: PMC3235380  PMID: 23024506
Phthiraptera; Lice; Amblycera; Prevalence; Myrsidea
10.  SERCA2 Regulates Non-CF and CF Airway Epithelial Cell Response to Ozone 
PLoS ONE  2011;6(11):e27451.
Calcium mobilization can regulate a wide range of essential functions of respiratory epithelium, including ion transport, ciliary beat frequency, and secretion of mucus, all of which are modified in cystic fibrosis (CF). SERCA2, an important controller of calcium signaling, is deficient in CF epithelium. We conducted this study to determine whether SERCA2 deficiency can modulate airway epithelial responses to environmental oxidants such as ozone. This could contribute to the pathogenesis of pulmonary exacerbations, which are important and frequent clinical events in CF. To address this, we used air-liquid interface (ALI) cultures of non-CF and CF cell lines, as well as differentiated cultures of cells derived from non-CF and CF patients. We found that ozone exposure caused enhanced membrane damage, mitochondrial dysfunction and apoptotic cell death in CF airway epithelial cell lines relative to non-CF. Ozone exposure caused increased proinflammatory cytokine production in CF airway epithelial cell lines. Elevated proinflammatory cytokine production also was observed in shRNA-mediated SERCA2 knockdown cells. Overexpression of SERCA2 reversed ozone-induced proinflammatory cytokine production. Ozone-induced proinflammatory cytokine production was NF-κB- dependent. In a stable NF-κB reporter cell line, SERCA2 inhibition and knockdown both upregulated cytomix-induced NF-κB activity, indicating importance of SERCA2 in modulating NF-κB activity. In this system, increased NF-κB activity was also accompanied by increased IL-8 production. Ozone also induced NF-κB activity and IL-8 release, an effect that was greater in SERCA2-silenced NF-κB-reporter cells. SERCA2 overexpression reversed cytomix-induced increased IL-8 release and total nuclear p65 in CFTR-deficient (16HBE-AS) cells. These studies suggest that SERCA2 is an important regulator of the proinflammatory response of airway epithelial cells and could be a potential therapeutic target.
PMCID: PMC3214057  PMID: 22096575
11.  Cardiorenal syndromes 
Cardiorenal syndromes (CRS) have been subclassified as five defined entities which represent clinical circumstances in which both the heart and the kidney are involved in a bidirectional injury and dysfunction via a final common pathway of cell-to-cell death and accelerated apoptosis mediated by oxidative stress. Types 1 and 2 involve acute and chronic cardiovascular disease (CVD) scenarios leading to acute kidney injury or accelerated chronic kidney disease. Types 2 and 3 describe acute and chronic kidney disease leading primarily to heart failure, although it is possible that acute coronary syndromes, stroke, and arrhythmias could be CVD outcomes in these forms of CRS. Finally, CRS type 5 describes a simultaneous insult to both heart and kidneys, such as sepsis, where both organs are injured simultaneously. Both blood and urine biomarkers are reviewed in this paper and offer a considerable opportunity to enhance the understanding of the pathophysiology and known epidemiology of these recently defined syndromes.
PMCID: PMC3030731  PMID: 21286212
Heart diseases; Kidney diseases; Cardiovascular diseases; Biological biomarkers; Creatinine
12.  Bio-Ecology of the Louse, Upupicola upupae, Infesting the Common Hoopoe, Upupa epops  
The population characteristics of the louse, Upupicola upupae (Shrank) (Mallophaga: Philopteridae: Ishnocera), infesting the Common Hoopae, Upupa epops L. (Aves: Upupiformes), were recorded during 2007–08 in District Rampur, Uttar Pradesh India. The pattern of frequency distribution of the louse conformed to the negative binomial model. The lice and its nits were reared in vitro at 35 ± 1° C, 75–82 % RH, on a feather diet. The data obtained was used to construct the life table and to determine the intrinsic rate of natural increase (0.035 female/day), the net reproductive rate was 3.67 female eggs/female, the generation time was 37 days, and the doubling time of the population was 19 days. The chaetotaxy of the three nymphal instars has also been noted to record their diagnostic characteristics. Information on egg morphology and antennal sensilla is also presented.
PMCID: PMC3281440  PMID: 21861650
Ischnocera; Phthiraptera; Upupicola upupae
13.  Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase Expression in Cystic Fibrosis Airways 
Rationale: Modulation of the activity of sarcoendoplasmic reticulum calcium ATPase (SERCA) can profoundly affect Ca2+ homeostasis. Although altered calcium homeostasis is a characteristic of cystic fibrosis (CF), the role of SERCA is unknown.
Objectives: This study provides a comprehensive investigation of expression and activity of SERCA in CF airway epithelium. A detailed study of the mechanisms underlying SERCA changes and its consequences was also undertaken.
Methods: Lung tissue samples (bronchus and bronchiole) from subjects with and without CF were evaluated by immunohistochemistry. Protein and mRNA expression in primary non-CF and CF cells was determined by Western and Northern blots.
Measurements and Main Results: SERCA2 expression was decreased in bronchial and bronchiolar epithelia of subjects with CF. SERCA2 expression in lysates of polarized tracheobronchial epithelial cells from subjects with CF was decreased by 67% as compared with those from subjects without CF. Several non-CF and CF airway epithelial cell lines were also probed. SERCA2 expression and activity were consistently decreased in CF cell lines. Adenoviral expression of mutant F508 cystic fibrosis transmembrane regulator gene (CFTR), inhibition of CFTR function pharmacologically (CFTRinh172), or stable expression of antisense oligonucleotides to inhibit CFTR expression caused decreased SERCA2 expression. In CF cells, SERCA2 interacted with Bcl-2, leading to its displacement from caveolae-related domains of endoplasmic reticulum membranes, as demonstrated in sucrose density gradient centrifugation and immunoprecipitation studies. Knockdown of SERCA2 using siRNA enhanced epithelial cell death due to ozone, hydrogen peroxide, and TNF-α.
Conclusions: Reduced SERCA2 expression may alter calcium signaling and apoptosis in CF. These findings decrease the likelihood of therapeutic benefit of SERCA inhibition in CF.
PMCID: PMC2675566  PMID: 19201925
cystic fibrosis; SERCA2; pulmonary epithelium; ER
14.  Khamiras, a natural cardiac tonic: An overview 
The Unani system of Medicine (Unanipathy), which originated in Greece, is based on the principles proposed by Galen, a Greek practitioner. Since then, many Arab and Persian scholars have contributed to the system. Among them Ibn-e-Sina, an Arab philosopher and Physicist who wrote ‘Kitab-al-shifa’ are worth mentioning. This system has an extensive and inspiring record in India. It was introduced in India around the tenth century A.D with the spread of Islamic civilization. At present, Unanipathy has become an important part of the Indian system of Medicine. Unani medicines have been used since ancient times, as medicines for the treatment of various ailments. In spite of the great advances observed in modern medicine in recent decades, Unani drugs still make an important contribution to healthcare. The Unani system of medicine is matchless in treating chronic diseases like arthritis, asthma, mental, cardiac, and digestive disorders, urinary infections, and sexual diseases. The medicines administered go well with the temperament of the patient, thus speeding up the process of recovery and also reducing the risk of drug reaction. The Unani system of medicine recognizes the influence of the surroundings and ecological conditions on the state of health of human beings. The system aims at restoring the equilibrium of various elements and faculties of the human body. It has laid down six essential prerequisites for the prevention of diseases and places great emphasis, on the one hand, on the maintenance of proper ecological balance, and on the other, on keeping water, food, and air free from pollution. These essentials, known as ‘Asbab-e-Sitta Zarooriya’, are air, food, and drink, bodily movement and repose, psychic movement and repose, sleep and wakefulness, and excretion and retention. The Unani system is a secular system in temperament and is popular among the masses. In Unani medicine, although the general preference is for single drugs, compound formulations are also used in the treatment of various complex and chronic disorders. In the light of the present knowledge, this review is a small effort to discuss the efficacious nature of ‘Khamira’, a semi-solid preparation, which is traditionally used for cardiac ailments, such as, palpitations, weakness of the heart, and so on. On the basis of their constituents these are named as, Khamira Aabresham, Khamira Gaozaban, Khamira Marwareed, and so on. Khameeras are also used as general tonics for other vital organs like the liver and brain. In view of the increasing number of cardiac diseases, a thorough evaluation of this ancient work on Khamira is of special significance.
PMCID: PMC3147110  PMID: 21814439
Cardiotonic; khameera; Unani system of medicine
15.  Population Characteristics and the Nature of Egg Shells of two Phthirapteran Species Parasitizing Indian Cattle Egrets 
The prevalence, intensities of infestation, range of infestation and population composition of two phthirapteran species, Ardeicola expallidus Blagoveshtchensky (Phthiraptera: Philopteridae) and Ciconiphilus decimfasciatus Boisduval and Lacordaire (Menoponidae) on seventy cattle egrets were recorded during August 2004 to March 2005, in India. The frequency distribution patterns of both the species were skewed but did not correspond to the negative binomial model. The oviposition sites, egg laying patterns and the nature of the eggs of the two species were markedly different.
PMCID: PMC3016757  PMID: 21067416
Amblycera; lschnocera; Ardeicola expallidus; Ciconiphilus decimfasciatus
16.  Pulmonary Embolectomy 
Western Journal of Medicine  1978;128(5):377-381.
Embolectomy was carried out in eight patients with pulmonary emboli. Angiographic diagnosis was obtained in six, and in two cases pulmonary angiography could not be done because of the very critical condition of the patients. In the latter two, diagnosis was made based only on clinical findings. Two patients died in the operating room (25 percent). Six patients were discharged in good condition.
It is emphasized that pulmonary embolectomy should be done in cases of pulmonary emboli when a clinical status of shock is present (systolic blood pressure less than 80 mm of mercury and the patient in low cardiac output syndrome) and when there is no response to medical treatment regardless of the degree of obstruction in the pulmonary arterial tree.
PMCID: PMC1238147  PMID: 664640

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