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Pulmonary & Critical Care Bulletin
Vol. VII, No. 3, July 15, 2001
In this issue :

From Editor's Desk

(Dr. Uma Maheswari,)

(R. S. Bedi & U.S. Bedi)

16th Annual Meeting on Pulmonary and Critical Care Medicine
(Dr. S. K. Jindal)

Publihed under the auspices of:
Pulmonary C. M. E. Programme

Editorial Board :

Department of Pulmonary Medecine
Post Graduate Institute of Medical Education & Research (PGIMER) Chandigarh. INDIA-160012

Subscription :

Pulmonary Interstitium

1. Definition

Pulmonary interstitium is the space interposed between the air space epithelium (from the main bronchi to the alveoli), the vascular endothelium and the pleural mesothelium.

II. Embryology and Constitution

It is the remnant of the splanchnopleuric mesenchymal bed into which the airway tubes and blood vessels have grown during the lung morphogenesis. It has got the following constituents : (I) Matric; (ii) Cells.

A. Interstitial Mesenchymal Cell

1. Fibroblasts - these are engaged in active fibrogenesis and secrete collagen, proteoglycans and fibronectin - important constituents of the connective tissue matrix.

2. Myofibroblasts - they have contractile properties due to the presence of actin and myosin in them. Their function is unclear.

3. Pericytes - these are myofibroblasts associated with capillaries.

4. Smooth muscle cells are fully differentiated contractile cells found in the free edges of alveolar septa where they are incorporated into the strong connective tissue fibre strands.

5. Undifferentiated mesenchymal cells are of a mixed cell population.

B. Interstitial Immune Cells

1. Mononuclear phagocytes - Morphologically, two types are easily recognized; alveolar macrophages and dendritic/ Langerhan's cells.

Alveolar macrophages have role in: a) defense against pathogens; b) ingestion and destruction of potential allergens; c) clearing of particulates and debris; d) presentation of antigens to T-lymphocytes; and e) clearing of antigens to regional lymph nodes. Dendritic/ Langerhan's cells are very efficient at presenting antigens to T-cells.

2. Lymphocytes - The ration of alveolar macrophages to lymphocytes is 1:5 to 1:10. The most common lymphocyte in the normal human alveolar interstitium is the T-cell, representing >95% of the lymphoctye population.

3. Mast Cells - secrete heparin and histamine

III Matrix Components

1. Fibrous System

To provide the lung with appropriate structural integrity, yet permit plastic deformation during respiration, the extracellular structure of the interstitium of alveolar walls evolved as a complete consortium of connective tissue matrix components. The alveolar surface, a) must withstand the distending pressure of the capillary blood due both to haemodynamic forces and gravity, b) must keep capillary bed expanded over a very large surface against the surface forces that act. This requires a very subtle economical design of fibrous support system without increasing the thickness of alveolar capillary interface.

An interstitial space with fibres and fibroblasts exists on only one side of the capillary, whereas on the other, the two lining cells, endothelium and epithelium become closely joined with only a single common basement membrane interposed. Over half of the surface of the capillary therefore, the blood is separated from the air merely by a minimal tissue barrier made of epithelial and endothelial cytoplasmic sheets with their basement membranes fused.

The principal structural `backbone' of the lung is a continuous system of fibres anchored at the hilum and put under tension by negative intrapleural pressure that tugs on the visceral pleura. There are two major components of fibre system.

(i). Axial Fibre System - forms `bark' of the tree whose roots are at the hilum and whose branches penetrate deep into the lung parenchyma, following the course of the airways.

(ii) Peripheral fibre system - related to visceral pleura, which penetrates into lung parenchyma separating units of the airway tree.

Thus the fibre system becomes a continuum that spans the entire space of the lung from the hilum to the visceral pleura.

There are two major types of fibres - collagen and elastic fibres. Collagen represents 15 - 20% of the dry weight of the lung. They are inextensible and have high tensile strength while elastic fibres are highly extensible and have low tensile strength. The major interstitial collagens are type I and III. Because of the association between `rubber like' elastic and `twine like' collagen fibres, the connective tissue strands behave like an elastic band, they are easy to stretch upto the point where the collagen fibres are taut, but from there on, they resist stretching very strongly.

The fibre-system along with surfactant, maintains the stability of the alveoli from collapsing. When an alveolus tends to shrink, the fibres in the wall of adjoining alveoli are stretched, and this will prevent the alveolus from collapsing. Thus the alveoli are mechanically interdependent.

In Interstitial lung disease, the focus of immunologic mechanism is the alveolar macrophage, which is activated, possibly by an immune complex and an as yet, unidentified antigen. Through mediators, termed chemokines, the macrophage attracts polymorphs and other cells from the circulation to the alveolar space, or it can initiate fibroensis with various mediators that can stimulate firboblasts and muscle cells to proliferate. This leads to interstitial fibrosis.

2. Fibronectin

The fibronectin molecule forms fibrils associated with matrix components and mesencymal cells in the interstitium. Through specific binding sites on the fibronectin molecules, it promotes cell adhesion and migration, cytodifferentiation, phagocytosis, and cell growth. Thee is increased staining of basal lamina in acute lung injury. There is increased level of fibronctin in brocho - alveolar lavage in fibrotic diseases of lung, sarcoidosis and paraquat poisoning. Animal experiments have found that decreased level of fibronectin is associated with decreased opsonic activity and infusion of fibronectin can reverse defect. In humans, severe sepsis is associated with decreased fibronectin plasma levels, but fibronectin replacement did not cause any significant decrease in moribidity and mortality.

3. Proteoglycans

These are a class of complex macromolecules comprised of a protein core and large sugars called `glycosaminoglycans'. In the alveolar wall, the major proteoglycans are heparan sulfate, chondroitin sulfate, and dermatan sulfate. Also included in this category is hyaluronic acid. While collagen fibres provide tensile strength and elastic fibres convey elastic recoil, the proteoglycans provide much of the bulk among the fibres. By virtue of their ability to take up water molecules, proteoglycans influence lung compliance and fluid balance. Elevation of level of hyaluronic acid has been noticed in conditions such as severe asthma, mesothelioma, squamous cell tumors, ARDS and emphysema. Hyaluronic acid level reaches a peak after 4 days of bleomycin injury. Increased chondroitin sulphate level is noticed in mesothelioma and in some cases of lung cancer. BAL has increased level of hyaluronic acid in idiopathic pulmonary fibrosis. In elastase induced emphysema, serial changes in various constituents of proteoglycans has been described.

4. Basement Membranes (BM)

The epithelial and endothelial basement membranes are continuous and form barriers defining the outer borders of the interstitium.

Functions of BM

Structural - Physical support for epithelial and endothelial cells
Barrier - To negatively charged macro molecules and prevents passage of non inflammatory cells
Celluar - Induces angiogenesis, development and regeneration and stimulates motility.

Components of BM Function
1. Collagen IV
2. Laminin
3. Heparan sulfate
4. Entactin/ nidogen
Cellular interactions
Charges shield, binds growth factors
Binds laminin and collagen IV

In Diabetes Mellitus thee is thickening of alveolar basement membrane due to non enzymatic glycosylation and is responsible for mild abnormalities in pulmonary function including decreased elastic recoil, decreased volumes, and decreased pulmonary diffusing capacity. In IPF and Hypersensitivity pneumonitis BM are disrupted in areas of intra alveolar fibrosis. In Goodpasture's syndrome there is linear immunoglobulin deposition along alveolar epithelial BM along with fragmentation. It is due to autoantibodies to globular domain of alpha - 3 chain of Type IV collagen. In asthma there is thickening of subepithelial BM as a sequela of protracted inflammation. In ARDS, there is diffuse disruption of BM leading to migration of connective tissue cells across basement membrane. This results is extensive air space and interstitial fibrosis in fibro-proliferative stage of ARDS.

Role of Pulmonary Interstitium in Liquid Exchange

The interstitial space is continuous with spaces around brochovascular bundles in the interlobular septa and under the visceral pleura. These spaces lead to lymphatic spaces. Every hour, 10-20 ml fluid is removed by lympthatics from interstitial space. This can increase 5 -10 times in pulmonary edema. Liquid exchanges between capillaries and interstitial space obey the Starling's law.

Liquid accumulation = K [ Pc - PIt) - (11c - 11it) ] Olymph

Gradient of hydrostatic pressure Between capillaries and interstitium

Gradient of oncotic pressure between capillaries and interstitium

Normal alveolar surface is free of fluid because of the tight junctions between epithelial and endothelial cells. Surfactant also plays a major role in keeping the alveoli dry. Rise in interstitial pressure producing a gradient above 20 mm Hg, may overcome these forces resulting in alveolar edema.

Dr. Balamugesh T.,
Senior Resident
Department of Pulmonary Medicine
PGI, Chandigarh

Dr. Balamugesh T.

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