Interstitial lung diseases.
ABSTRACT Several noninfectious nonneoplastic interstitial lung diseases (ILDs) have been recognized in dogs and cats. Overall, these ILDs are poorly characterized in dogs and cats, although awareness of the conditions based on descriptions of clinical case series may be increasing. Lung biopsy remains crucial to the diagnosis, characterization, and classification of ILDs. Histopathologic findings can help to guide clinicians in selecting appropriate therapy and providing an accurate prognosis to pet owners. Only with definitive recognition of these pulmonary conditions can our knowledge of the clinical course and response to therapy be improved.
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ABSTRACT: Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial lung disease affecting mainly middle-aged and old West Highland white terriers. Other dogs, especially terriers, have been diagnosed with the disease. The cause is largely unknown, but it is likely to arise from interplay between genetic and environmental factors. CIPF shares several features with human idiopathic pulmonary fibrosis. This article summarizes the current literature; describes the findings in physical examination, arterial blood gas analysis, bronchoscopy, bronchoalveolar lavage, diagnostic imaging, and histopathology; compares the canine and human diseases; gives an overview of potential treatments; and discusses biomarker research.Veterinary Clinics of North America Small Animal Practice 01/2014; 44(1):129-142. · 1.43 Impact Factor
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ABSTRACT: Infiltration of T lymphocytes in the lungs is common in patients with and in animal models of pulmonary fibrosis. The role of these cells in regulating the accumulation of extracellular matrix, particularly collagen, is not understood completely. Research literature provides evidence for a profibrotic, an antifibrotic, or no significant role of T lymphocytes in pulmonary fibrosis. This review offers a discussion of such evidence with the focus on phenotypes of pulmonary T lymphocytes and related profibrotic and antifibrotic mechanisms. It appears unlikely that T lymphocytic infiltration per se is the central driving force in most cases of pulmonary fibrosis. Instead, evidence suggests that T lymphocytes may modulate the inflammatory and healing responses in the lungs in a profibrotic or antifibrotic manner, depending on their phenotype. Phenotypic reshaping, rather than elimination of the infiltrating pulmonary T lymphocytes, may be a promising approach to improving outcomes in patients with pulmonary fibrosis.Journal of Leukocyte Biology 03/2008; 83(2):237-44. · 4.57 Impact Factor
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ABSTRACT: Pulmonary diseases associated with fibrosis, including scleroderma lung disease, are characterized by the accumulation of T cells in the lungs. These cells are thought to facilitate lung fibrosis, but the exact mechanisms of their profibrotic action are not clear. Several alphaV-containing integrins, including alphaVbeta3 and alphaVbeta5, have been shown to directly activate transforming growth factor beta (TGFbeta) and promote collagen accumulation. The aim of this study was to investigate whether pulmonary T cells express profibrotic integrins and regulate collagen accumulation. Expression of integrins was assessed by immunohistochemical analysis of lung tissue, by flow cytometry using bronchoalveolar lavage fluid from patients with systemic sclerosis (SSc), and in a CCL18 overexpression animal model of pulmonary T cell infiltration. Experiments in cell cultures were performed to determine whether integrin-expressing T cells are profibrotic in cocultures with pulmonary fibroblasts and, if so, through what possible mechanism. Lymphocytes and integrin-positive cells were present in the lungs, and pulmonary T cells expressed integrins alphaVbeta3 and alphaVbeta5 in patients with SSc and in the animal model. Systemic administration of neutralizing anti-integrin alphaV antibody or a genetic deficiency of integrin beta3 in the CCL18 overexpression model significantly attenuated CCL18-driven pulmonary lymphocytic infiltration and collagen accumulation. Jurkat T cells overexpressing integrin alphaVbeta3 or integrin alphaVbeta5 in cocultures with primary pulmonary fibroblasts stimulated collagen accumulation and Smad2 nuclear translocation. Neutralizing anti-TGFbeta antibody attenuated the profibrotic effect of integrin-expressing T cells. Pulmonary infiltrating T lymphocytes may express integrins alphaVbeta3 and alphaVbeta5 that are necessary for lymphocytic infiltration and T cell-associated TGFbeta activation and collagen accumulation.Arthritis & Rheumatology 05/2009; 60(5):1530-9. · 7.48 Impact Factor
Interstitial Lung Diseases
University of Missouri-Columbia, Department of Veterinary Medicine and Surgery
Columbia, MO, USA
OBJECTIVES OF THE PRESENTATION
To familiarize veterinarians with interstitial lung diseases, a heterogenous group of non-infectious
inflammatory conditions affecting the pulmonary parenchyma.
Interstitial lung diseases should be considered as differential diagnoses in dogs and cats with clinical
signs of cough or respiratory distress, radiographic evidence of interstitial to alveolar infiltrates, and
cytology which is non-specific (i.e., not infectious or neoplastic).
OVERVIEW OF THE ISSUE
Disorders of the pulmonary parenchyma are frequently diagnosed in dogs and cats. The most common
types of pulmonary parenchymal disease recognized in small animals include infectious pneumonia
(bacterial, fungal, viral, protozoal, parasitic or rickettsial) or neoplasia (primary or metastatic). The
interstitial lung diseases (ILDs) are a heterogenous group of non-infectious respiratory tract disorders
with overlapping clinical and radiographic features. Definitive diagnosis requires a lung biopsy.
Compared with infectious pneumonia and neoplasia, they are poorly characterized and hence,
underdiagnosed in dogs and cats.
Interstitial lung diseases (ILDs) are associated with disruption of the distal pulmonary parenchyma, with
pathology centering around the interstitium (i.e., the anatomic space between the basement membrane of
the alveolar epithelial cells and capillary endothelial cells). Many of the ILDs arise from injury to the
alveolar epithelial lining which triggers a host inflammatory response and reparative events that lead to a
variety of structural changes. This injury can be derived from inhalation of substances (e.g., allergens,
mineral fibers or dusts), or the injury may come through the blood vessels with vascular damage from
occurring from drugs, toxins, or immune disease. The etiology of ILDs in humans is frequently idiopathic
where no specific cause of the injury is ever identified. This is also likely true in dogs and cats 1-4.
The pulmonary inflammatory cascade triggered by parenchymal injury is intended to repair and
restore normal function to the tissue. However, the chronic inflammation and fibrosis associated with
ILDs is a result of dysregulated and exaggerated host tissue repair; that is, the self-limiting inflammatory
response has been replaced by a cycle of inflammation and collagen deposition. Cells of the innate and
adaptive immune system work in concert to orchestrate the chronic changes seen in ILDs. Initially when
the tissue is injured, elaboration of vasoactive and chemotactic molecules enables leukocyte infiltration
into the damaged pulmonary parenchyma. Neutrophils are the earliest inflammatory cell to arrive at the
site of injury, and rely on cell adhesion molecules to localize in the pulmonary vasculature and
chemoattractants to gain access to the interstitium and alveolar spaces. Neutrophils contain a variety of
preformed toxic particles in their granules (e.g., elastase, cathepsin G, and collagenase) and can generate
toxic oxygen radicals that allow further tissue damage and attract other inflammatory cells. In some ILDs,
eosinophils are important mediators of tissue damage, and may respond to many of the same
chemoattractants as neutrophils. Degranulation of eosinophils causes release of a wide variety of
inflammatory mediators, and these cells are postulated to be of critical importance in type I
hypersensitivity diseases in the lung. Macrophages are also attracted to sites of tissue injury, and can
elaborate a wide range of proinflammatory and profibrotic cytokines. They play a key role in regulation
of the fibrotic response, allowing for a net accumulation of collagen (i.e., an increase in collagen synthesis
and a decrease in collagen degradation) in diseases like IPF. Lymphocytes are also recognized in
cytologic or histologic specimens from patients with some ILDs. T cells in particular may be critical in the
modulation of inflammation and fibrosis by virtue of the cytokines they secrete. They are also central
players in type IV hypersensitivity (delayed type hypersensitivity, DTH) pneumonitis.
ILDs Recognized in Dogs and Cats
While there are over 160 different specific causes of ILDs in humans, only a limited number of ILDs have
been described in dogs and cats. Most of these have been reported in the literature as single case reports
and include eosinophilic pneumonia, pulmonary interstitial fibrosis (including idiopathic pulmonary
fibrosis or IPF), lymphocytic interstitial pneumonitis (LIP), bronchiolitis obliterans with organizing
pneumonia (BOOP), silicosis, and asbestosis1-7.
Diagnosis of ILDs
Although in humans many of the ILDs are so well classified that a diagnosis can be reached using
signalment, history, high resolution computed tomography (HRCT), bronchoalveolar lavage fluid (BALF)
analysis, and results of pulmonary function testing, histologic examination of lung tissue remains the
gold standard for diagnosis at this time. The value of lung biopsy in the diagnosis of respiratory tract
disease in dogs and cats with non-diagnostic thoracic radiography and BALF cytology has been
previously described 1,2. Lung biopsy in animals with ILDs is instrumental to confirm the diagnosis, select
appropriate therapy, and guide the clinician in giving an appropriate prognosis to owners.
In dogs and cats with clinical signs of pulmonary parenchymal disease, diagnostic evaluation may reveal
an interstitial to alveolar radiographic pattern and cytologic evidence of non-specific inflammation. When
infectious agents or neoplastic cells can not be seen cytologically, interstitial lung disease is a strong
consideration. Lung biopsy is required to definitively diagnose ILDs, and further classify them to guide
the clinician in providing the patient with appropriate therapy and prognosis. The underlying etiology of
most ILDs in dogs and cats is unknown (idiopathic), with non-specific injury to pulmonary epithelial
cells triggering an inflammatory cascade intended to be reparative. However, when the inflammation
becomes dysregulated, the injury is perpetuated resulting in an ILD. Further research is necessary to help
clinicians understand more about how the injury is created and perpetuated, so that appropriate therapy
can interrupt the inflammatory cascade.
1. Norris C, Griffey S, Samii V, et al. Comparison of results of thoracic radiography, cytologic evaluation of
bronchoalveolar lavage fluid, and histologic evaluation of lung specimens in dogs with respiratory tract disease:
16 cases (1996-2000). J Am Vet Med Assoc 2001;218:1456-1461.
2. Norris C, Griffey S, Samii V, et al. Thoracic radiography, bronchoalveolar cytology, and pulmonary
parenchymal histology: a comparison of diagnostic results in 11 cats. J Am Anim Hosp 2002;38:337-345.
3. Lobetti R, Milner R, Lane E. Chronic idiopathic pulmonary fibrosis in five dogs. J Am Anim Hosp Assoc
4. Phillips S, Barr S, Dykes N, et al. Bronchiolitis obliterans with organizing pneumonia in a dog. J Vet Intern Med
5. Cadore J, Steiner-Laurent S, Greenland T, et al. Interstitial lung disease in feline immunodeficiency virus (FIV)
infected cats. Res Vet Sci 1997;62:287-288.
6. Canfield P, Rothwell T, Padpdimitriou J, et al. Siliceous pneumoconiosis in two dogs. J Comp Path 1989;89:199-
7. Norris C, Mellema M. Eosinophilic pneumonia In: King L, ed. Textbook of respiratory diseases in dogs and cats.
Philadelphia: WB Saunders Co., 2004;541-547.