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Chakradhar Kotaru

Publications and source records attributed to Chakradhar Kotaru.

5 recordsLinked to original sources
PubMed2006

Regional fibroblast heterogeneity in the lung: implications for remodeling.

RATIONALE: Excessive deposition of extracellular matrix occurs in proximal airways of individuals with asthma, but fibrosis in distal lung has not been observed. Whether differing fibrotic capacities of fibroblasts from these two regions contribute to this variability is unknown. OBJECTIVES: We compared morphologic and functional characteristics of fibroblasts isolated from proximal airways and distal lung parenchyma to determine phenotypic differences. METHODS: Concurrent proximal airway and distal lung biopsies were obtained by bronchoscopy from subjects with asthma to isolate airway and distal lung fibroblasts, respectively. The following characteristics were compared: morphology, proliferation, alpha-smooth muscle actin expression, and synthesis of procollagen type I and eotaxin-1. RESULTS: Airway fibroblasts (AFs) are morphologically distinct from distal lung fibroblasts (DLFs): they are larger (2.3-fold greater surface area vs. matched DLFs; p = 0.02), stellate in appearance, and with more cytoplasmic projections compared with the spindle-shaped DLFs. AFs synthesized more procollagen type I than did DLFs at baseline (twofold higher; p = 0.003) and after transforming growth factor-beta stimulation (1.4-fold higher; p = 0.02). Similarly, AFs produced more eotaxin-1 than did DLFs at baseline (2.5-fold higher; p = 0.004) and after interleukin-13 stimulation (13-fold higher; p = 0.0001). In contrast, DLFs proliferate more than AFs with serum stimulation (about sixfold greater; p = 0.03). Unstimulated DLFs also expressed more alpha-smooth muscle actin than did corresponding AFs (p = 0.006). CONCLUSIONS: These studies suggest that at least two phenotypes of fibroblast exist in the lung. These phenotypic differences may partially explain the variable responses to injury and repair between proximal airways and distal lung/parenchyma in asthma and other respiratory diseases.

Actins↗
PubMed2005

Defective apoptotic cell phagocytosis attenuates prostaglandin E2 and 15-hydroxyeicosatetraenoic acid in severe asthma alveolar macrophages.

RATIONALE: Clearance of apoptotic cells is crucial to the resolution of inflammation and development of fibrosis, but the process is not well understood in normal or diseased human lungs. OBJECTIVES: To determine phagocytosis of apoptotic cells by primary human alveolar macrophages and whether defects in uptake of apoptotic cells are associated with decreases in antiinflammatory/antifibrotic mediators. METHODS: Human bronchoalveolar lavage macrophages (AMphis) from normal control subjects and subjects with mild-moderate or severe asthma were examined in vitro for phagocytosis of apoptotic human T-cell line Jurkats and secretion of inflammatory mediators. MEASUREMENTS AND MAIN RESULTS: AMphis from normal subjects and patients with mild-moderate asthma were able to phagocytose apoptotic cells in response to LPS, resulting in an induction of the antifibrotic and/or antiinflammatory eicosanoids, prostaglandin E2 (PGE2) and 15-hydroxyeicosatetraenoic acid (HETE). In contrast, AMphis from patients with severe asthma had defective LPS-stimulated uptake of apoptotic cells, with associated failure to induce PGE2 and 15-HETE. In addition, LPS-stimulated basal levels of tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor were reduced in all patients with asthma, whereas PGE2 and 15-HETE were reduced only in patients with severe asthma. Dexamethasone enhanced specific uptake of apoptotic cells in all subjects, while suppressing inflammatory mediator secretion. CONCLUSIONS: A decrease in AMphis LPS-responsiveness in severe asthma is manifested by defective apoptotic cell uptake and reduces secretion of inflammatory mediators. This may contribute to the chronicity of inflammation and remodeling in lungs of patients with asthma.

Adult↗
PubMed2004

Morphometric changes after thermal and methacholine bronchoprovocations.

To determine whether there are distinctions in the location and pattern of response between different bronchoprovocations, we performed high-resolution computer-assisted tomography in 10 asthmatic subjects before and after isocapnic hyperventilation of frigid air (HV) and methacholine (Meth). The luminal areas of the trachea, main stem, lobar, and segmental bronchi were computed before and after each provocation and blindly compared. Both stimuli reduced the 1-s forced expiratory volume similarly (percent change in 1-s forced expiratory volume HV = 28.1 +/- 5.5%, Meth = 25.8 +/- 5.2%; P = 0.69) but did so in different fashions. Each provocation was associated with the development of both bronchial narrowing and dilation; however, more airways constricted with HV (67.7%) than with Meth (47.0%; P < 0.001). Furthermore, there was little concordance between either the magnitude or direction of change between stimuli in any region of the lung (r = 0.25). In general, the frequency of narrowing increased with branching. Constriction became more prominent in the lobar regions and increased further in the segmental branches, but a wide range of intensity existed. These data demonstrate that provocational stimuli evoke complex morphometric changes within the tracheobronchial tree and that different agonists produce different patterns. Thermal stimuli chiefly influence the segmental level, whereas the response to Meth develops more distally. Even within this distribution, the same airway does not respond in an identical fashion to different stimuli, so there does not appear to be a uniform trigger zone.

Adult↗
PubMed2002

Desiccation and hypertonicity of the airway surface fluid and thermally induced asthma.

To determine whether drying and hypertonicity of the airway surface fluid (ASF) are involved in thermally induced asthma, nine subjects performed isocapnic hyperventilation (HV) (minute ventilation 62.2 +/- 8.3 l/min) of frigid air (-8.9 +/- 3.3 degrees C) while periciliary fluid was collected endoscopically from the trachea. Osmolality was measured by freezing-point depression. The baseline 1-s forced expiratory volume was 73 +/- 4% of predicted and fell 26.4% 10 min postchallenge (P > 0.0001). The volume of ASF collected was 11.0 +/- 2.2 microl at rest and remained constant during and after HV as the airways narrowed (HV 10.6 +/- 1.9, recovery 6.5 +/- 1.7 microl; P = 0.18). The osmolality also remained stable throughout (rest 336 +/- 16, HV 339 +/- 16, and recovery 352 +/- 19 mosmol/kgH(2)O, P = 0.76). These data demonstrate that airway desiccation and hypertonicity of the ASF do not develop during hyperpnea in asthma; therefore, other mechanisms must cause exercise- and hyperventilation-induced airflow limitation.

Adult↗